4-aryl-1-phenylalkyl-1,2,3,6-tetrahydropyridines having neurotrophic and neuroprotective activity

ABSTRACT

The present invention relates to the compounds of formula (I) ##STR1## wherein Y is --CH-- or --N--; R 1  is hydrogen, a halogen or a CF 3 , (C 3  -C 4 )alkyl or (C 1  -C 4 )alkoxy group; R 2  is hydrogen, a halogen, a hydroxyl or a CF 3 , (C 3  -C 4 )alkyl or (C 1  -C 4 )alkoxy group; R 3  and R 4  are each hydrogen or a (C 1  -C 3 )alkyl; and X is (a) a (C 3  -C 6 )alkyl, a (C 3  -C 6 )alkoxy, a (C 3  -C 7 )carboxyalkyl, a (C 1  -C 4 )-alkoxycarbonyl(C 3  -C 6 )alkyl, a (C 3  -C 7 )carboxyalkoxy or a (C 1  -C 4 )alkoxycarbonyl(C 3  -C 6 )alkoxy; (b) a radical selected from a (C 3  -C 7 )cycloalkyl, (C 3  -C 7 )cycloalkoxy, (C 3  -C 7 )cycloalkylmethyl, (C 3  -C 7 )cycloalkylamino and cyclohexenyl, it being possible for said radical to be substituted by a halogen, hydroxyl, (C 1  -C 4 )alkoxy, carboxyl, (C 1  -C 4 )alkoxycarbonyl, amino or mono- or di-(C 1  -C 4 )alkylamino; or (c) a group selected from a phenyl, phenoxy, phenylamino, N-(C 1  -C 3 )alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl, phenylthio, phenylsulfonyl, phenylsulfinyl and styryl, it being possible for said group to be monosubstituted or polysubstituted on the phenyl group by a halogen, CF 3 , (C 1  -C 4 )alkyl, (C 1  -C 4 )alkoxy, cyano, amino, mono- or di-(C 1  -C 4 )alkylamino, (C 1  -C 4 )acylamino, carboxyl, (C 1  -C 4 )-alkoxycarbonyl, aminocarbonyl, mono- or di-(C 1  -C 4 )-alkyl-aminocarbonyl, amino(C 1  -C 4 )alkyl, hydroxy(C 1  -C 4 )alkyl or halogeno(C 1  -C 4 )alkyl, as well as the salts and solvates thereof and the quaternary ammonium salts thereof; to a process for their preparation and to pharmaceutical compositions containing them. 
     These compounds have a neurotrophic and neuroprotective activity.

This application is a 371 of PCT/FR96/00995 filed Jun. 26, 1996.

The present invention relates to novel 4-substituted1-phenylalkyl-1,2,3,6-tetrahydropyridines with a neurotrophic andneuroprotective activity, to a process for their preparation and topharmaceutical compositions in which they are present.

EP-0 458 696 describes the use of a1-(2-naphthylethyl)-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinefor the preparation of drugs for the treatment of cerebral and neuronaldisorders.

WO 93/11107 describes piperidines and tetrahydropyridines with aprotective activity on the damage caused by hypoxic/ischemic states.

It has now been found that certainphenylalkyl-1,2,3,6-tetrahydropyridines substituted by a phenyl orpyridyl group exert a neurotrophic action on the nervous system which issimilar to the action of nerve growth factor (NGF), and can restorefunction to cells which are damaged or exhibit anomalies in theirphysiological functions.

According to one of its features, the present invention thereforerelates to the compounds of formula (I): ##STR2## in which Y is --CH--or --N--;

R₁ is hydrogen, a halogen or a CF₃, (C₃ -C₄)alkyl or (C_(1-C) ₄)alkoxygroup;

R₂ is hydrogen, a halogen, a hydroxyl or a CF₃, (C₃ -C₄)alkyl or (C₁-C₄)alkoxy group;

R₃ and R₄ are each hydrogen or a (C₁ -C₃)alkyl; and

X is

(a) a (C₃ -C₆)alkyl, a (C₃ -C₆)alkoxy, a (C₃ -C₇) carboxyalkyl, a (C₁-C₄)alkoxycarbonyl(C₃ -C₆)alkyl, a (C₃ -C₇)carboxyalkoxy or a (C₁-C₄)alkoxycarbonyl(C₃ -C₆)alkoxy;

(b) a radical selected from a (C₃ -C₇)cycloalkyl, (C₃ -C₇)cycloalkoxy,(C₃ -C₇)cycloalkylmethyl, (C₃ -C₇)cycloalkylamino and cyclohexenyl, itbeing possible for said radical to be substituted by a halogen,hydroxyl, (C₁ -C₄)alkoxy, carboxyl, (C₁ -C₄)alkoxycarbonyl, amino ormono- or di-(C₁ -C₄)alkylamino; or

(c) a group selected from a phenyl, phenoxy, phenylamino, N-(C₁-C₃)alkylphenylamino, phenylmethyl, phenylethyl, phenylcarbonyl,phenylthio, phenylsulfonyl, phenylsulfinyl and styryl, it being possiblefor said group to be monosubstituted or polysubstituted on the phenylgroup by a halogen, CF₃, (C₁ -C₄)alkyl, (C₁ -C₄)alkoxy, cyano, amino,mono- or di-(C₁ -C₄)alkylamino, (C₁ -C₄)acylamino, carboxyl, (C₁-C₄)alkoxycarbonyl, aminocarbonyl, mono- or di-(C₁-C₄)alkylaminocarbonyl, amino(C₁ -C₄)alkyl, hydroxy(C₁ -C₄)alkyl orhalogeno(C₁ -C₄)alkyl, the salts and solvates thereof and the quaternaryammonium salts thereof.

In the present description the term "(C₁ -C₃)alkyl" denotes methyl,ethyl, n-propyl and i-propyl groups.

The term "(C₁ -C₄)alkyl" denotes methyl, ethyl, n-propyl, i-propyl,n-butyl, i-butyl, s-butyl and t-butyl groups.

The term "(C₃ -C₆)alkyl" denotes a saturated or unsaturated hydrocarbonradical containing from 3 to 6 carbon atoms, such as, for example,n-propyl, i-propyl, n-butyl, i-butyl, s-butyl, t-butyl, n-pentyl,i-pentyl, neopentyl, t-pentyl, n-hexyl, i-hexyl etc.

The term "alkoxy" denotes a hydroxyl group substituted by an alkyl,alkenyl or alkynyl group.

If X is a phenyl group, the nomenclature used for the biphenyl radicalconforms to the IUPAC rules, i.e. the numbering of the positions of thetwo rings is as follows: ##STR3## and the radicals having this structureare named as follows: ##STR4##

The compounds of formula (I) in which X is in the 4-position of thephenyl group, and the salts thereof, especially those which arepharmaceutically acceptable, the solvates thereof and the quaternaryammonium salts thereof, are particularly advantageous compounds.

One preferred group of compounds among those of formula (I) in which Xis a group (c) is represented by the compounds in which the phenyl issubstituted by 1 to 3 halogen, 1 to 3 CF₃, 1 to 3 (C₁ -C₄)alkyl, 1 to 3(C₁ -C₄)alkoxy, 1 to 3 cyano, 1 to 3 amino, 1 to 3 mono- or di-(C₁-C₄)alkylamino, 1 to 3 (C₁ -C₄)acylamino, 1 to 3 carboxyl, 1 to 3 (C₁-C₄)alkoxycarbonyl, 1 to 3 aminocarbonyl, 1 to 3 mono- or di-(C₁-C₄)alkylaminocarbonyl, 1 to 3 amino(C₁ -C₄)alkyl, 1 to 3 hydroxy(C₁-C₄)alkyl or 1 to 3 halogeno(C₁ -C₄)alkyl.

Another preferred group consists of the compounds of formula (I) inwhich Y is a group --CH-- and R₁ is CF₃.

Another preferred group consists of the compounds of formula (I) inwhich Y is a nitrogen atom and R₁ is a chlorine atom.

The following are particularly advantageous compounds according to thepresent invention:

1-[2-(4-isobutylphenyl)propyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[(2S)-2-(4-isobutylphenyl)propyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[(2R)-2-(4-isobutylphenyl)propyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-isobutylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-tert-butylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-isobutylphenyl)-2-methyipropyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-isopropylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3'-chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(2'-chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4'-chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4'-fluorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3'-trifluoromethylbiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-cyclohexylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(biphenyl-4-yl)-2-ethyl]-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(biphenyl-4-yl)-2-methylpropyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-phenoxyphenyl)-2-ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-benzylphenyl)-2-ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-n-butylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(biphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-n-butoxyphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-(3-ethoxycarbonylpropoxy)phenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(biphenyl-4-yl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine;

1-[2-(2,3'-dichlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3-chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3',5'-dichlorobiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(2',4'-dichlorobiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(2-chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3'-chlorobiphenyl-4-yl)-2-methylpropyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(2-fluorobiphenyl-4-yl)propyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-methoxybiphenyl-3-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4'-methoxybiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4'-hydroxybiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4'-ethoxycarbonylbutoxybiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(biphenyl-3-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3'-chloro-4'-fluorobiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(2'-trifluoromethylbiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3,4-diisobutylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(3,4-dipropylphenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-cyclohexylphenyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine;

1-[2-(4-isobutylphenyl)propyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine;

and the salts thereof.

According to another of its features, the present invention relates to aprocess for the preparation of the compounds of formula (I), the saltsor solvates thereof and the quaternary ammonium salts thereof, wherein

(a) an aryl-1,2,3,6-tetrahydropyridine of formula (II): ##STR5## inwhich Y and R₁ are as defined above, is reacted with a compound offormula (III): ##STR6## in which R₂, R₃, R₄ and X are as defined aboveand L is a leaving group such as, for example, a chlorine, bromine oriodine atom or the methanesulfonyloxy, p-toluenesulfonyloxy ortrifluoromethylsulfonyloxy group; and

(b) the resulting compound of formula (I) is isolated and optionallyconverted to a salt or solvate thereof or a quaternary ammonium saltthereof.

The reaction is carried out in an organic solvent at a temperaturebetween room temperature and the reflux temperature of the solvent used.

The organic solvent used is preferably an aliphatic alcohol having from1 to 6 carbon atoms, such as methanol, ethanol, isopropanol, n-butanolor n-pentanol, but it is also possible to use other solvents such ashexane, dimethylformamide, dimethylsulfoxide, sulfolane, acetonitrile,pyridine and the like.

The reaction is advantageously carried out in the presence of a basicagent such as an alkali metal carbonate or triethylamine, especially inthe case where L is a halogen atom.

The reaction temperature can vary between room temperature (about 20°C.) and the reflux temperature, the reaction times varying accordingly.In general, after 6 to 12 hours of refluxing, the reaction has ended andthe final product obtained can be isolated by the conventionaltechniques in the form of the free base or a salt thereof, the free baseoptionally being converted to a salt thereof by simple salification inan organic solvent such as an alcohol, preferably ethanol orisopropanol, an ether like 1,2-dimethoxy-ethane, ethyl acetate, acetoneor a hydrocarbon like hexane.

Alternatively the compounds of formula (I) in which Y is --CH--, thesalts or solvates thereof and the quaternary ammonium salts thereof canbe prepared by a process wherein

(a) the compound of formula (IV): ##STR7## in which R₁ is as definedabove, is reacted with a functional derivative of the acid of formula(V): ##STR8## in which R₂, R₃, R₄ and X are as defined above, (b) thecarbonyl group of the compound of formula (VI): ##STR9## is reduced, (c)the intermediate piperidinol of formula (VII): ##STR10## is dehydratedand (d) the resulting compound of formula (I) is isolated and optionallyconverted to a salt or solvate thereof or a quaternary ammonium saltthereof.

The reaction of step (a) can conveniently be carried out in an organicsolvent at a temperature between -10° C. and the reflux temperature ofthe reaction mixture.

Appropriate functional derivatives of the acid of formula (V) which canbe used are the free acid (optionally activated with BOP, for example),the anhydride, a mixed anhydride, an active ester or an acid halide,preferably the bromide. Of the active esters the p-nitrophenyl ester isparticularly preferred, but the methoxyphenyl, trityl, benzhydryl andsimilar esters are also suitable.

The reaction temperature can vary between -10° C. and the refluxtemperature, but the reaction is generally carried out at roomtemperature or at 30-50° C. It can be preferable to carry out thereaction in the cold if it is exothermic, as in the case where thechloride is used as the functional derivative of the acid of formula(V).

The reaction solvent used is preferably a halogenated solvent such asmethylene chloride, dichloroethane, 1,1,1-trichloroethane, chloroform orthe like, or an alcohol such as methanol or ethanol, but it is alsopossible to employ other organic solvents compatible with the reactantsused, for example dioxane, tetrahydrofuran or a hydrocarbon such ashexane.

The reaction can conveniently be carried out in the presence of a protonacceptor, for example an alkali metal carbonate or a tertiary amine.

The reduction of step (b) can conveniently be carried out withappropriate reducing agents such as borane complexes, for exampleborane/dimethyl sulfide, aluminum hydrides or a complex lithium aluminumhydride, in an inert organic solvent at a temperature between 0° C. andthe reflux temperature of the reaction mixture, using the customarytechniques.

"Inert organic solvent" is understood as meaning a solvent which doesnot interfere with the reaction. Examples of such solvents are etherslike diethyl ether, tetrahydrofuran, dioxane or 1,2-dimethoxyethane.

In a preferred mode of carrying out the invention, the reaction isperformed with borane/dimethyl sulfide used in excess relative to theinitial compound (VI), at the reflux temperature, optionally under aninert atmosphere. The reduction has normally ended after a few hours.

The dehydration of step (c) is easy to carry out, for example using anacetic acid/sulfuric acid mixture at a temperature between roomtemperature and the reflux temperature of the solvent used.

In a preferred method, the reaction of step (c) is carried out in anacetic acid/sulfuric acid mixture in a volume ratio of 1/3, the reactionmixture being heated at a temperature of about 110° C. for 1-3 hours.

The desired compound is isolated by the conventional techniques in theform of the free base or a salt thereof. The free base can be convertedto a salt thereof by simple salification in an organic solvent such asan alcohol, preferably ethanol or isopropanol, an ether like1,2-dimethoxyethane, ethyl acetate, acetone or a hydrocarbon likehexane.

The compound of formula (I) obtained is isolated by the customarytechniques and optionally converted to an acid addition salt thereof or,if there is an acid group present, the amphoteric character of thecompound enables the salts to be separated with either acids or bases.

The compounds of formulae (VI) and (VII), which can be jointlyrepresented by formula (i): ##STR11## in which R₁, R₂, R₃, R₄, X and Yare as defined above and W is a methylene group or a carbonyl group,said compounds being key intermediates in the synthesis of the compoundsof formula (I), are novel compounds and constitute a further subject ofthe present invention.

If salts of the compound of formula (I) are prepared for administrationas drugs, the acids or bases employed must be pharmaceuticallyacceptable; if salts of the compound of formula (I) are prepared foranother purpose, for example to improve the purification of the productor to facilitate analytical assays, any acid or base can then be used.

Examples of the salts with pharmaceutically acceptable bases are thosewith alkali or alkaline earth metals such as sodium, potassium, calciumor magnesium, and those with organic bases such as amines, basic aminoacids (lysine, arginine, histidine), trometamol, N-methylglutamine, etc.

Examples of the salts with pharmaceutically acceptable acids are thosewith mineral acids, such as the hydrochloride, hydrobromide, borate,phosphate, sulfate, hydrogensulfate and hydrogenphosphate, and thosewith organic acids, such as the citrate, benzoate, ascorbate,methylsulfate, naphthalene-2-sulfonate, picrate, fumarate, maleate,malonate, oxalate, succinate, acetate, tartrate, mesylate, tosylate,isethionate, α-ketoglutarate, α-glycerophosphate, glucose-1-phosphate,etc.

The starting amines of formula (II) in which Y is --CH-- are knowncompounds or can be prepared by processes analogous to those used toprepare known compounds.

The starting amines of formula (II) in which Y is N can be prepared byreacting the appropriate 2-halogenopyridine of formula (p): ##STR12##with a 1,2,3,6-tetrahydropyridine of formula (q): ##STR13## in which P°is a protecting group, such as the benzyl group, and Z is a substituentwhich permits nucleophilic substitution of the halogen on the pyridine.Examples of such substituents are trialkylstannanes, such astributylstannane, or Grignard compounds.

The 1,2,3,6-tetrahydropyridine is then deprotected by cleavage of theprotecting group under suitable conditions.

The amines of formula (II') below: ##STR14## in which R₁ ' is a halogen,CF₃, (C₃ -C₄)alkyl or (C₁ -C₄)alkoxy, and the salts thereof, are novelcompounds and constitute a further subject of the present invention.

The compounds of formula (III) can be prepared

either by reducing the acids of formula (V) to the alcohol andconverting the hydroxyl group to a leaving group;

or, to prepare a compound of formula (III) in which R₃ =R₄ =H, byreacting the appropriate benzene of formula (r): ##STR15## in which R₂and X are as defined above, with an acyl halide of the formula L--CH₂--CO--Hal, in the presence of a Lewis acid, according to the well-knownFriedel-Crafts reaction, and reducing the resulting ketone of formula(s): ##STR16## by the procedures widely described in the literature.

The acids of formula (V) are generally compounds which are described inthe literature. A large number of these compounds are generallydescribed as antiinflammatories, examples being hexaprofen, tetriprofen,alclofenac, butiprofen, mexoprofen, ibufenac, ibuprofen, flurbiprofen,phenoprofen, fenclofenac, etc.

The starting materials (III) and (V) in which X is an optionallysubstituted phenyl group can also be prepared by an original process,Suzuki's reaction being carried out in an aqueous medium in a novelprocess which constitutes a further subject of the present invention.

Thus, according to another of its features, the present inventionrelates to a process for the preparation of biphenylyl derivatives bymeans of a condensation reaction between phenyl derivatives substitutedby a leaving group and benzeneboronic acids in the presence of acatalyst, a strong base and a phase transfer agent.

The present invention therefore also relates to a process for thepreparation of the compounds of formula (t) below: ##STR17## in whichthe benzene can optionally be substituted and X' is a phenyl optionallymonosubstituted or polysubstituted by a halogen, CF₃, (C₁ -C₄)alkyl, (C₁-C₄)alkoxy, cyano, amino, mono- or di-(C₁ -C₄)alkylamino, (C₁-C₄)acylamino, carboxyl, (C₁ -C₄)alkoxycarbonyl, aminocarbonyl, mono- ordi-(C₁ -C₄)alkylaminocarbonyl, amino(C₁ -C₄)alkyl, hydroxy(C₁ -C₄)alkylor halogeno(C₁ -C₄)alkyl, said process consisting in reacting a compoundof formula (w): ##STR18## in which the benzene can optionally besubstituted and L' is a leaving group as defined above for L, with abenzeneboronic acid of the formula X'--B(OH)₂, in which X' is as definedabove, in the presence of a palladium salt, a strong base and a phasetransfer agent, in an aqueous medium.

More particularly, and according to an advantageous feature, the presentinvention relates to a process for the preparation of the compounds offormula (t'): ##STR19## in which R₂, R₃, R₄ and X' are as defined aboveand G is a carboxyl group or a group L--CH₂ --, in which L is a leavinggroup as defined above, which process consists in reacting a compound offormula (w'): ##STR20## in which R₂, R₃, R₄, G and L' are as definedabove, with a benzeneboronic acid of the formula X'--B(OH)₂, in which X'is as defined above, in the presence of a palladium salt, a strong baseand a phase transfer agent, in an aqueous medium.

Preferred leaving groups L' are bromine and thetrifluoromethylsulfonyloxy group.

Palladium acetate is a preferred palladium salt.

Examples of strong bases which can be used are alkali metal hydroxidesor carbonates such as sodium hydroxide or carbonate or potassiumhydroxide or carbonate.

Phase transfer agents which can be used are tetraalkylammonium halides,tetrabutylammonium bromide being particularly advantageous.

The reaction is advantageously carried out by heating the mixture tobetween 30° C. and the reflux point, especially to between 50° C. and80° C. and preferably to about 70° C.

The reaction finishes rapidly, normally in a few hours, depending on theoperating temperature.

The products of formula (t') and the acids of the formula X'--B(OH)₂ areknown in the literature or can be prepared by methods analogous to thoseused for known compounds. Synthesis Examples are nevertheless includedin the experimental section of the present description.

The activity of the compounds of formula (I) on the nervous system wasdemonstrated in in vitro and in vivo studies using the methods describedin EP-0 458 696 and, for evaluation of the neuronal survival, by meansof an in vitro survival test conducted using neurons isolated from thedissected septal region of rat embryos.

More particularly, the septal region of 17- to 18-day-old rat embryoswas removed under a dissecting microscope under sterile conditions andthen dissociated in a trypsin/EDTA medium. The cell suspension wasplaced in a culture flask in a DME/Ham's F12 (v:v) medium (DulbeccoModified Eagle's Medium/Ham's F12 Nutrient Mixture--R. G. Ham, Proc.Nat. Sci., 1965, 53:288) containing 5% calf serum and 5% horse serum,and maintained at 37° C. for 90 minutes. This treatment makes itpossible to eliminate the non-neuronal cells.

The neuroblasts are then inoculated into the wells of a titer plate at arate of 17×10⁴ cells/cm², in a non-serum culture medium consisting ofDME/Ham's F12 containing selenium (30 nM) and transferrin (1.25 μM).Each well has first been treated with poly-L-lysine. The inoculatedplates are placed in an incubator in the oven (37° C.; 5% CO₂).

The test compounds are dissolved in DMSO and diluted with the culturemedium as required.

The neuroblasts are kept for 4 days in plates containing the testcompound or the corresponding solvent, without changing the medium.

After 4 days the medium is replaced with a tetrazolium salt dissolved inthe culture medium (0.15 mg/ml). The cells are then placed in the ovenat 37° C. for 4 hours. The mitochondrial succinate dehydrogenases of thelive cells reduce the tetrazolium salt to formazan blue, the opticaldensity of which is measured at 540 nm after dissolution in DMSO; saiddensity has a linear correlation with the number of live cells(Manthorpe et al., Dev. Brain Res., 1988, 25:191-198).

The difference between the groups containing the test compounds and thecontrols was evaluated by statistical analysis using the two-tailedDunnett t-test.

In said test the compounds of formula (I) proved as active as or moreactive than the compounds described in EP-0 458 696, the efficacy ofsome compounds of formula (I) in respect of neuronal survival beingdouble that of compound A described in EP-0 458 696.

By virtue of this potent neuroprotective activity and their lowtoxicity, which is compatible with their use as drugs, the compounds offormula (I), the pharmaceutically acceptable addition salts thereof, thesolvates thereof and the quaternary ammonium salts thereof can be usedfor the preparation of pharmaceutical compositions indicated in thetreatment and/or prophylaxis of all diseases which involve neuronaldegeneration. More particularly, the compounds of the invention can beused, either by themselves or in co-administration or association withother active principles acting on the CNS, for example selective M1cholinomimetics, NMDA antagonists or nootropics such as piracetam,especially in the following indications: memory disorders, vasculardementia, postencephalitic disorders, postapoplectic disorders,posttraumatic syndromes due to a cranial traumatism, disorders derivingfrom cerebral anoxia, Alzheimer's disease, senile dementia, subcorticaldementia such as Huntington's chorea and Parkinson's disease, dementiacaused by AIDS, neuropathy deriving from morbidity or damage to thesympathetic or sensory nerves, brain diseases such as cerebral edema,spinocerebellar degenerations and motor neuron degenerations such as,for example, amyotrophic lateral sclerosis.

According to another feature, the invention relates to a method oftreating the above-mentioned complaints which consists in administeringto a patient in need a therapeutically effective amount of a compoundaccording to the invention, as such or mixed with conventionalpharmaceutical carriers.

The compounds of the invention can conveniently be administered orally,parenterally, sublingually or transdermally. The amount of activeprinciple to be administered in the treatment of cerebral and neuronaldisorders by the method of the present invention depends on the natureand severity of the complaints to be treated and on the weight of thepatients. Nevertheless the preferred unit doses will generally comprisefrom 0.5 to 700 mg of product, advantageously from 2 to 300 mg andpreferably from 5 to 150 mg, for example between 5 and 50 mg, namely 1,2, 5, 10, 15, 20, 25, 30, 40 or 50 mg. These unit doses will normally beadministered one or more times a day, for example 2, 3, 4 or 5 times aday and preferably one to three times a day, the overall human dosevarying between 1 and 1400 mg per day and advantageously between 2 and900 mg per day, for example from 3 to 500 mg and more conveniently from10 to 300 mg per day.

In the pharmaceutical compositions of the present invention for oral,sublingual, subcutaneous, intramuscular, intravenous, transdermal orrectal administration, the active principle can be administered toanimals and humans in unit forms of administration, either as such, forexample in lyophilized form, or mixed with conventional pharmaceuticalcarriers, for the treatment of the above-mentioned complaints. Theappropriate unit forms of administration include oral forms such astablets, which may be divisible, gelatin capsules, powders, granules andsolutions or suspensions to be taken orally, sublingual and buccal formsof administration, subcutaneous, intramuscular or intravenous forms ofadministration, local forms of administration and rectal forms ofadministration.

When a solid composition in the form of tablets is prepared, the mainactive ingredient is mixed with a pharmaceutical vehicle such asgelatin, starch, lactose, magnesium stearate, talc, gum arabic or thelike. The tablets can be coated with sucrose or other appropriatesubstances or else they can be treated so as to have a prolonged ordelayed activity and so as to release a predetermined amount of activeprinciple continuously.

A preparation in the form of gelatin capsules is obtained by mixing theactive ingredient with a diluent and pouring the mixture obtained intosoft or hard gelatin capsules.

A preparation in the form of a syrup or elixir can contain the activeingredient together with a sweetener, which is preferably calorie-free,methylparaben and propylparaben as antiseptics, a flavoring and anappropriate color.

The water-dispersible granules or powders can contain the activeingredient mixed with dispersants or wetting agents or with suspendingagents such as polyvinylpyrrolidone, as well as with sweeteners or tastecorrectors.

Rectal administration is effected using suppositories, which areprepared with binders melting at the rectal temperature, for examplecocoa butter or polyethylene glycols.

Parenteral administration is effected using aqueous suspensions, salinesolutions or sterile and injectable solutions which containpharmacologically compatible dispersants and/or wetting agents, forexample propylene glycol or butylene glycol.

The active principle can also be formulated as microcapsules, with oneor more carriers or additives if appropriate.

In the pharmaceutical compositions according to the present invention,the active principle can also be in the form of an inclusion complex incyclodextrins or ethers or esters thereof.

The Examples which follow illustrate the invention more clearly withouthowever implying a limitation.

PREPARATION 1

2-Trifluoromethylbenzeneboronic acid

1.36 ml (0.01 mmol) of 2-bromotrifluoromethylbenzene and 10 ml ofanhydrous ethyl ether are mixed under an argon atmosphere. The mixtureis cooled to 0° C., 7 ml of BuLi (1.6 M solution in hexane) are addedand the mixture is left at a temperature of 0° C. for 2 hours. It isthen transferred to a solution of 3 ml of triisopropylborate (0.0125mol) and 15 ml of anhydrous THF at -78° C. under an argon atmosphere.

The mixture is left at -78° C. for 3 hours and then at room temperatureovernight. It is poured into 1 N aqueous hydrochloric acid solution andextracted with ethyl ether, the organic phase is dried over sodiumsulfate and the solvent is evaporated off under reduced pressure.

The residue is treated with hexane and the precipitate formed isfiltered off to give 0.7 g of the title compound. M.p.=140-143° C.

PREPARATION 2

3-Chlorobenzeneboronic acid

The title compound is obtained by following the procedure described inPreparation 1 but using 3-bromochlorobenzene instead of2-bromotrifiuoromethylbenzene. M.p.=176-178° C.

PREPARATION 3

(2-Chloro-4-methoxyphenyl)acetic acid

3i/2-Chloro-4-methoxyacetophenone

14.3 g (0.11 mol) of 3-chloroanisole are added at 0° C. to a mixture of9.3 ml (0.13 mol) of acetyl chloride and 350 ml of methylene chloride.The mixture is stirred for 1 hour and then, with the temperaturemaintained at 0° C., 24 g (0.18 mol) of aluminum chloride are added andthe reaction is allowed to proceed at this temperature for 2 hours. 20ml of 1 N hydrochloric acid solution and 20 ml of water are then added.The two phases are separated, the organic phase is washed with water,dried over sodium sulfate and filtered and the solvent is evaporated offunder reduced pressure. The crude product is purified by chromatographyon a silica gel column using an 8/2 cyclohexane/ethyl acetate mixture asthe eluent to give the title compound.

3ii/4-(2-Chloro-4-methoxybenzylthiocarbonyl)morpholine

A mixture of 5.52 g (0.03 mol) of the product of the previous step, 7.1ml of morpholine and 1.15 g of sulfur is heated at 130° C. for 4 hours.1 N hydrochloric acid solution is then added and the mixture isextracted with ethyl acetate. The two phases are separated, the organicphase is dried over sodium sulfate and the solvent is evaporated offunder reduced pressure. The crude product is treated with 2.5 ml ofethyl acetate and the precipitate formed is filtered off to give thetitle compound. M.p.=100-102° C.

3iii/(2-Chloro-4-methoxyphenyl)acetic acid

A mixture of 6.6 g of the product of the previous step, 35 ml of ethanoland a solution of 3 g of sodium hydroxide in 55 ml of water is refluxedfor 8 hours. It is washed with ethyl ether and the aqueous solution isacidified with 1 N hydrochloric acid and extracted with ethyl ether. Theorganic phase is dried over sodium sulfate and filtered and the solventis evaporated off under reduced pressure to give the title compound.M.p.=115-117° C.

PREPARATION 4

(2-Chloro-4-hydroxyphenyl)acetic acid

A solution of 1.6 g (8 mmol) of (2-chloro-4-methoxyphenyl)acetic acid,prepared according to Preparation 3, in 13 ml of hydrobromic acid (in48% aqueous solution) is refluxed for two hours. After cooling, ammoniumhydroxide is added until the pH is basic, and the mixture is extractedwith methylene chloride. The water is evaporated from the aqueous phaseand the residue is washed several times with ethanol to give the titlecompound.

EXAMPLE 1

1-[2-(4-Isobutylphenyl)propyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride 1a/Ethyl2-(4-isobutylphenyl)propionate

Gaseous hydrochloric acid is bubbled for one hour into a solution of 50g (0.242 mol) of 2-(4-isobutylphenyl)propionic acid in 700 ml ofabsolute ethanol and the mixture is then refluxed for two hours. Thesolvent is evaporated off and the residue is taken up with ethylacetate. The mixture is washed with aqueous sodium bicarbonate solutionand dried over sodium sulfate and the solvent is evaporated off underreduced pressure to give the title compound.

1b/2-(4-Isobutylphenyl)propyl alcohol

A solution of 59 g (0.25 mol) of the compound of the previous step in450 ml of ethyl ether is added under nitrogen to a suspension of 9.55 gof lithium aluminum hydride in 50 ml of ethyl ether, the temperaturebeing maintained at 20° C. The reaction mixture is stirred at roomtemperature for 2 hours and a solution of 60 ml of 95% ethanol and 60 mlof water is then added, with extreme caution, to destroy the unreactedhydride. The salts formed are filtered off and the filtrate isevaporated under reduced pressure to give the title compound.

1c/2-(4-Isobutylphenyl)propyl methanesulfonate

A mixture of 15.5 g (0.08 mol) of the compound of the previous step, 100ml of methylene chloride and 24.2 g (0.1774 mol) of triethylamine iscooled to 0-5° C. and a solution of 12.9 g (0.1774 mol) of mesylchloride in 10 ml of methylene chloride is added. The mixture is stirredat room temperature for 5 hours. The solution is then washed with 1 Nhydrochloric acid solution, with water, with aqueous sodium bicarbonatesolution and again with water. The organic phase is dried over sodiumsulfate and the solvent is evaporated off under reduced pressure to givethe title compound.

1d/1-[2-(4-Isobutylphenyl)propyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

A mixture of 2.63 g (0.01 mol) of4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine, 4.2 ml (0.03mol) of triethylamine and 4 g (0.01 mol) of2-(4-isobutylphenyl)-1-(methylsulfonyloxy)propane in 40 ml ofisopropanol is refluxed overnight. The solvent is evaporated off underreduced pressure and the residue is purified by chromatography on asilica gel column using an 8/2 cyclohexane/ethyl acetate mixture as theeluent. The hydrochloride of the resulting oil is prepared with asolution of hydrochloric acid in ethyl ether. The precipitate obtainedis filtered off and then crystallized from acetone. M.p.=190-192° C.

EXAMPLE 2

1-[(2S)-2-(4-Isobutylphenyl)propyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride2a/1-[(2S)-2-(4-Isobutylphenyl)propionyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine

2.06 g (0.01 mol) of (2S)-2-(4-isobutylphenyl)propionic acid, 35 ml ofmethylene chloride, 2.09 g (0.015 mol) of triethylamine, 2.45 g (0.01mol) of 4-(3-trifluoromethylphenyl)-4-piperidinol and 4.42 g (0.01 mol)of BOP are mixed and the solution is stirred at room temperature for 1.5hours. Ethyl acetate is then added and the mixture is washed with water,with 1 N hydrochloric acid, with water, with 1 N sodium hydroxide andwith water. The organic phase is dried over sodium sulfate and thesolvent is evaporated off under reduced pressure. The resulting crudeoil is purified by chromatography on a silica gel column using a 9/1ethyl acetate/cyclohexane mixture as the eluent. 3.3 g of the titleproduct are isolated. M.p.=123-125° C. [α]_(D) ²⁰ =-66.70° (c =1%,MeOH).

2b/1-[(2S)-2-(4-Isobutylphenyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidinehydrochloride

3.0 g (0.0069 mol) of the product of the previous step in 30 ml oftetrahydrofuran are heated to the reflux point and 2.09 ml (0.02 mol) ofborane/dimethyl sulfide in 20 ml of tetrahydrofuran are added. Themixture is refluxed for 4 hours, the solution is cooled to 10-15° C. and15 ml of methanol are cautiously added dropwise. The mixture is stirredfor 15 minutes at room temperature and then for 30 minutes under reflux.The solvent is evaporated off under reduced pressure and the residue istaken up with dilute aqueous ammonia solution. The mixture is extractedwith ethyl acetate, the organic phase is washed with water and driedover sodium sulfate and the solvent is evaporated off under reducedpressure to give 3.0 g of a crude oil. The hydrochloride is prepared bytreatment with a saturated solution of hydrochloric acid in isopropanolto give the title compound. M.p.=250-252° C. [α]_(D) ²⁰ =+35.01° (c=1%,MeOH).

2c/1-[(2S)-2-(4-Isobutylphenyl)propyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

1.3 g (0.0023 mol) of the product of the previous step are dissolved in10 ml of acetic acid, 3 ml of 96% sulfuric acid are added and themixture is heated at 110° C. for 2 hours. It is poured into a water/icemixture, concentrated sodium hydroxide solution is added and theresulting mixture is extracted with ethyl ether. The organic phase iswashed with water and dried over sodium sulfate and the solvent isevaporated off under reduced pressure to give 1.25 g of a crude oil. Thehydrochloride is prepared by treatment with a saturated solution ofhydrochloric acid in isopropanol to give the title compound, which iscrystallized from acetone. M.p.=223-225° C. [α]_(D) ²⁰ =+46.8° (c=1%,MeOH).

EXAMPLE 3

1-[(2R)-2-(4-Isobutylphenyl)propyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride3a/1-[(2R)-2-(4-Isobutylphenyl)propionyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine

The title product is obtained by following the procedure described inExample 2a but using (2R)-2-(4-isobutylphenyl)propionic acid.M.p.=122-124° C. [α]_(D) ²⁰ =+68.7° (c=1%, MeOH).

3b/1-[(2R)-2-(4-Isobutylphenyl)propyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidinehydrochloride

The title product is obtained by following the procedure described inExample 2b using the compound of step 3a. M.p.=257-260° C. [α]_(D) ²⁰=-37.2° (c=1%, MeOH).

3c/1-[(2R)-2-(4-Isobutylphenyl)propyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

The title product is obtained by following the procedure described inExample 2c using the compound of step 3b. M.p.=224-226° C. [α]_(D) ²⁰=-45.6° (c=1%, MeOH).

EXAMPLE 4

1-[2-(4-Isobutylphenyl)ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride4a/1-Bromo-2-(4-isobutylphenyl)ethane

A mixture of 5 g (0.0373 mol) of isobutylbenzene, 67 ml of methylenechloride and 9.86 g (0.0489 mol) of bromoacetyl bromide is cooled to0-5° C. and 5.75 g (0.0431 mol) of aluminum trichloride are added. Themixture is stirred at 0-5° C. for one hour and then left at roomtemperature overnight. It is poured into a water/ice mixture andextracted with methylene chloride, the organic phase is dried oversodium sulfate and the solvent is evaporated off under reduced pressure.4.6 g (0.018 mol) of the resulting oil are mixed with 9.7 ml (0.123 mol)of trifluoroacetic acid and 12.7 ml (0.0792 mol) of triethylsilane andthe mixture is heated at 80° C. for 4 hours. Saturated aqueous sodiumbicarbonate solution is then added until the pH is basic, the mixture isextracted with ethyl ether, the organic phase is dried over sodiumsulfate and the solvent is evaporated off under reduced pressure. Theresulting crude oil is purified by chromatography on a silica gel columnusing cyclohexane as the eluent to give the title compound. Thin layerchromatography (eluent: cyclohexane): Rf=0.5.

4b/1-[2-(4-Isobutylphenyl)ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride

A mixture of 2.5 g (0.0095 mol) of 4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine, 50 ml of butanol, 3.94 g(0.0285 mol) of anhydrous potassium carbonate chips and 2.3 g (0.0095mol) of the product of the previous step is refluxed for 8 hours. Thesolvent is evaporated off under reduced pressure, the residue is takenup with ethyl acetate, the mixture is washed with water and dried oversodium sulfate and the solvent is evaporated off under reduced pressure.The hydrochloride of the resulting oil is prepared by treatment with asaturated solution of hydrochloric acid in isopropanol to give 2.4 g ofthe title compound, which is crystallized from isopropanol.M.p.=242-246° C. Thin layer chromatography (eluent: cyclohexane/ethylacetate=1/1): Rf=0.6.

EXAMPLE 5

1-[2-(4-Tert-butylphenyl)ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride5a/1-Bromo-2-(4-tert-butylphenyl)ethane

The title product is obtained by following the procedure described inExample 4a but using tert-butylbenzene instead of isobutylbenzene. Thinlayer chromatography (eluent: cyclohexane): Rf=0.6.

5b/1-[2-(4-Tert-butylphenyl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

The title compound is obtained by following the procedure described inExample 4b using the compound of step 5a. M.p.=261-265° C. Thin layerchromatography (eluent: cyclohexane/ethyl acetate=1/1): Rf=0.7.

EXAMPLE 6

1-[2-(4-Isobutylphenyl)-2-methylpropyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine oxalate6a/2-(4-Isobutylphenyl)-2-methylpropionic acid

5 g (0.0227 mol) of ethyl 2-(4-isobutylphenyl)propionate (Example 1a)are dissolved in 50 ml of DMF, and 1.6 g (0.025 mol) of sodium hydrideare added in portions. After 30 minutes 3.2 ml (0.0375 mol) of methyliodide are added. The mixture is stirred at room temperature for 2hours, poured into a water/ice mixture and extracted with ethyl acetate,the extract is washed with water and dried over sodium sulfate and thesolvent is evaporated off under reduced pressure. 5.7 g of the resultingoil are mixed with 5.7 g of potassium hydroxide, 35 ml of water and 35ml of absolute ethanol and the mixture is refluxed for 2 hours. Theethanol is evaporated off under reduced pressure, the residue is washedwith ethyl acetate, the aqueous phase is acidified with hydrochloricacid and extracted with ethyl acetate, the organic phase is dried oversodium sulfate and the solvent is evaporated off to give the titlecompound in the form of a semisolid oil.

6b/1-[2-(4-Isobutylphenyl)-2-methylpropionyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine

2.86 g (0.013 mol) of the acid of the previous step, 45 ml of methylenechloride, 2.7 ml (0.0195 mol) of triethylamine, 3.18 g (0.013 mol) of4-hydroxy-4-(3-trifluoromethylphenyl)piperidine and 5.74 g (0.013 mol)of BOP are mixed and the mixture is stirred at room temperature for 1.5hours. The solvent is evaporated off under reduced pressure, the residueis taken up with ethyl acetate, the mixture is washed with water, with 1N hydrochloric acid, with water, with 1 N sodium hydroxide and withwater, the organic phase is dried over sodium sulfate and filtered andthe solvent is evaporated off to give an oil. This is crystallized fromisopropyl ether to give 1.5 g of the title compound. M.p.=158-160° C.Thin layer chromatography (eluent: cyclohexane/ethyl acetate=7/3):Rf=0.4.

6c/1-[2-(4-Isobutylphenyl)-2-methylpropyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidinehydrochloride

2.78 g (0.00622 mol) of the compound of the previous step in 30 ml oftetrahydrofuran are heated to the reflux point and 1.9 ml (0.0186 mol)of borane/dimethyl sulfide in 20 ml of tetrahydrofuran are added, refluxbeing maintained for 4 hours. The solution is cooled to 10-15° C., 15 mlof methanol are added and the mixture is stirred for 15 minutes at roomtemperature and 30 minutes under reflux. The solvent is evaporated offunder reduced pressure, the residue is taken up with water (15 ml),concentrated ammonium hydroxide is added until the pH is basic, themixture is extracted with ethyl acetate, the extract is washed withwater, the organic phase is dried over sodium sulfate and the solvent isevaporated off under reduced pressure to give 3 g of an oil. This issalified by treatment with a saturated solution of hydrochloric acid inisopropanol to give 1.4 g of the title compound. M.p.=263-265° C. Thinlayer chromatography (eluent: cyclohexane/ethyl acetate=7/3): Rf=0.3(base).

6d/1-[2-(4-Isobutylphenyl)-2-methylpropyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine oxalate

1.2 g (0.0025 mol) of the compound of the previous step, 10 ml ofglacial acetic acid and 3 ml of 96% sulfuric acid are refluxed for 2hours. The mixture is poured into a water/ice mixture, 20% sodiumhydroxide solution is added until the pH is basic, the resulting mixtureis extracted with ethyl acetate, the organic phase is washed with waterand dried over sodium sulfate and the solvent is evaporated off underreduced pressure to give an oil. This is treated with oxalic acid inisopropanol to give the title compound. M.p.=164-165° C.

EXAMPLE 7

1-[2-(4-Isopropylphenyl)ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride7a/1-Bromo-2-(4-isopropylphenyl)ethane

A mixture of 4.6 g (0.030 mol) of cumene, 50 ml of methylene chlorideand 2.86 ml (0.033 mol) of bromoacetyl bromide is cooled to 0-5° C. and4 g (0.030 mol) of aluminum trichloride are added. The mixture isstirred at 0-5° C. for one hour and then stirred at room temperature for4 hours. It is poured into a water/ice mixture and extracted withmethylene chloride, the organic phase is dried over sodium sulfate andthe solvent is evaporated off under reduced pressure. 8.5 g of theresulting oil are mixed with 19 ml (0.246 mol) of trifluoroacetic acidand 24.6 ml (0.154 mol) of triethylsilane and the mixture is heated at80° C. for 4 hours. Saturated aqueous sodium bicarbonate solution isthen added until the pH is basic, the mixture is extracted with ethylacetate, the organic phase is dried over sodium sulfate and the solventis evaporated off under reduced pressure to give 10 g of the titlecompound.

7b/1-[2-(4-Isopropylphenyl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

A mixture of 3.7 g (0.014 mol) of 4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine, 74 ml of butanol, 4.8 g(0.035 mol) of anhydrous potassium carbonate chips and 4 g (0.018 mol)of the product of the previous step is refluxed for 5 hours. The solventis evaporated off under reduced pressure, the residue is taken up withethyl acetate, the mixture is washed with water and dried over sodiumsulfate and the solvent is evaporated off under reduced pressure. Thehydrochloride of the resulting oil is prepared by treatment with asaturated solution of hydrochloric acid in isopropanol to give 2 g ofthe title compound, which is crystallized from isopropanol.M.p.=262-263° C. Thin layer chromatography (eluent: cyclohexane/ethylacetate=1/1): Rf=0.7.

EXAMPLE 8

1-[2-(3'-Chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine

8a/1-Bromo-2-(3'-chlorobiphenyl-4-yl)ethane

A mixture of 5 g (0.026 mol) of 3-chlorobiphenyl, 50 ml of methylenechloride and 6.95 g (0.034 mol) of bromoacetyl bromide is cooled to 0-5°C. and 4 g (0.030 mol) of aluminum trichloride are added. The mixture isstirred for 4 hours at room temperature. It is poured into a water/icemixture and extracted with methylene chloride and the organic phase iswashed with 1 N HCl solution, dried over sodium sulfate and evaporatedunder reduced pressure. 7 g of the resulting oil are mixed with 12.1 ml(0.156 mol) of trifluoroacetic acid and 15.8 ml (0.0986 mol) oftriethylsilane and the mixture is heated at 80° C. for 4 hours.Saturated aqueous sodium bicarbonate solution is then added until the pHis basic, the mixture is extracted with ethyl ether, the organic phaseis washed with sodium bicarbonate solution and dried over sodium sulfateand the solvent is evaporated off under reduced pressure to give thetitle compound.

8b/1-[2-(3'-Chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine

A mixture of 2.63 g (0.010 mol) of4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine, 80 ml ofbutanol, 3.5 g (0.025 mol) of anhydrous potassium carbonate chips and2.63 g of the product of the previous step is refluxed for 5 hours. Thesalts are filtered off, the solvent is evaporated off under reducedpressure, the residue is taken up with ethyl acetate, the mixture iswashed with water and dried over sodium sulfate and the solvent isevaporated off under reduced pressure. The crude product is purified bychromatography on a silica gel column using a 3/7 ethylacetate/cyclohexane mixture as the eluent. Rf=0.5. 2 g of the titlecompound are obtained. M.p.=85-87° C.

EXAMPLE 9

1-[2-(2'-Chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride9a/1-Bromo-2-(2'-chlorobiphenyl-4-yl)ethane

8 g of the title compound are obtained by following the proceduredescribed in Example 8a but using 5 g of 2-chlorobiphenyl instead of3-chlorobiphenyl.

9b/1-[2-(2'-Chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

Crude 1-[2-(2'-chlorobiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine is obtained by followingthe procedure described in Example 8b but using the compound of step 9a.This is purified by chromatography on a silica gel column using a 2/8ethyl acetate/cyclohexane mixture as the eluent; Rf=0.5. Thehydrochloride is prepared with a saturated solution of hydrochloric acidin isopropanol. The resulting product is crystallized from isopropanolto give 5 g of the title compound. M.p.=227-230° C.

EXAMPLE 10

1-[2-(4'-Chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine10a/1-Bromo-2-(4'-chlorobiphenyl-4-yl)ethane

The title compound is obtained by following the procedure described inExample 8a but using 5 g of 4-chlorobiphenyl instead of3-chlorobiphenyl.

10b/1-[2-(4'-Chlorobiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine

The crude title compound is obtained by following the proceduredescribed in Example 8b but using the compound of step 10a. This ispurified by chromatography on a silica gel column using a 2/8 ethylacetate/cyclohexane mixture as the eluent; Rf=0.5. 4 g of the titlecompound are obtained in the form of a white solid, which iscrystallized from ethyl acetate. M.p.=146-148° C.

EXAMPLE 11

1-[2-(4'-Fluorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride11a/1-Bromo-2-(4'-fluorobiphenyl-4-yl)ethane

The title compound is obtained by following the procedure described inExample 8a but using 4-fluorobiphenyl instead of 3-chlorobiphenyl.

11b/1-[2-(4'-Fluorobiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

Crude1-[2-(4'-fluorobiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineis obtained by following the procedure described in Example 8b but usingthe compound of step 11a. The hydrochloride is prepared with a saturatedsolution of HCl in isopropanol. This gives the title compound, which iscrystallized from isopropanol. M.p.=257-259° C. Thin layerchromatography (eluent: cyclohexane/ethyl acetate=1/1): Rf=0.5.

EXAMPLE 12

1-[2-(3'-Trifluoromethylbiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

The title compound is obtained by following the procedure described inExample 8 but starting from 3-trifluoromethylbiphenyl instead of3-chlorobiphenyl. M.p.=229-233° C.

EXAMPLE 13

1-[2-(4-Cyclohexylphenyl)ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride13a/1-Bromo-2-(4-cyclohexylphenyl)ethane

5.56 g of the title compound are obtained by following the proceduredescribed in Example 8a but using 10 g of cyclohexylbenzene instead of3-chlorobiphenyl.

13b/1-[2-(4-Cyclohexylphenyl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

Crude 1-[2-(4-cyclohexylphenyl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine is obtained by followingthe procedure described in Example 8b but using the compound of step13a. This is purified by chromatography on a silica gel column using a9/1 cyclohexane/ethyl acetate mixture as the eluent. The hydrochlorideis prepared with a saturated solution of hydrochloric acid inisopropanol to give 2.55 g of the title compound. M.p.=255-260° C. Thinlayer chromatography (eluent: cyclohexane/ethyl acetate=7/3): Rf=0.5.

EXAMPLE 14

1-[2-(Biphenyl-4-yl)-2-ethyl]-4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridineoxalate

A mixture of 1 g (0.0047 mol) of4-(4-fluorophenyl)-1,2,3,6-tetrahydropyridine, 20 ml of butanol, 1.6 g(0.012 mol) of anhydrous potassium carbonate chips and 1.2 g of1-bromo-2-(biphenyl-4-yl)ethane is refluxed for 5 hours. The salts arefiltered off, the solvent is evaporated off under reduced pressure, theresidue is taken up with ethyl acetate, the mixture is washed with waterand dried over sodium sulfate and the solvent is evaporated off underreduced pressure. The oxalate of the resulting oil is prepared bytreatment with oxalic acid in acetone. This gives the title compound,which is crystallized from ethanol. M.p.=211-215° C. Thin layerchromatography (eluent: ethyl acetate/cyclohexane=1/1): Rf=0.6.

EXAMPLE 15

1-[2-(Biphenyl-4-yl)-2-methylpropyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride 15a/Ethylbiphenyl-4-ylacetate

45 g of biphenyl-4-ylacetic acid (0.212 mol) are dissolved in 650 ml ofabsolute ethanol. Gaseous hydrochloric acid is bubbled into the solutionfor 1 hour and the solution is then refluxed for 2 hours. The ethanol isevaporated off, the residue is taken up with ethyl acetate and themixture is washed with aqueous sodium bicarbonate solution and then withwater. The organic phase is dried over sodium sulfate and the solvent isevaporated off under reduced pressure to give 40 g of the titlecompound.

15b/α,α-Dimethylbiphenyl-4-ylacetic acid

10.8 g (0.0449 mol) of the product of the previous step are dissolved in100 ml of dimethylformamide. The mixture is cooled to 0-5° C. and 5.04 gof 55% sodium hydride are added in small portions. The mixture isstirred at room temperature for 30 minutes. It is cooled again to 0-5°C., 7.9 ml of methyl iodide are added dropwise and the mixture isstirred at room temperature for 3 hours. It is poured into a water/icemixture and extracted with ethyl acetate, the extract is washed withwater, the organic phase is dried over sodium sulfate and the solvent isevaporated off under reduced pressure. The resulting oil is dissolved ina solution of 12 g of sodium hydroxide in 70 ml of water and 70 ml of95% ethanol. The reaction medium is refluxed for 2 hours, the ethanol isevaporated off under reduced pressure and the aqueous phase is washedwith ethyl acetate. The aqueous solution is acidified with concentratedhydrochloric acid and the precipitate formed is filtered off to give 8.2g of the title compound, which is crystallized from 500 ml of 50%ethanol. M.p.=152-157° C.

15c/1-[2-(Biphenyl-4-yl)-2-methylpropionyl]-4-hydroxy-4-(3-trifluoromethylphenyl)pyridine

3.6 g (0.015 mol) of the product of the previous step, 60 ml ofmethylene chloride, 6.3 ml (0.045 mol) of triethylamine, 4.2 g (0.015mol) of 4-(3-trifluoromethylphenyl)-4-piperidinol hydrochloride and 6.6g (0.015 mol) of BOP are mixed and the mixture is stirred at roomtemperature for 1.5 hours. The solvent is evaporated off under reducedpressure, the residue is taken up with ethyl acetate and the mixture iswashed with water, then with 1 N hydrochloric acid solution, with water,with 1 N sodium hydroxide solution and again with water. The organicphase is dried over sodium sulfate and the solvent is evaporated offunder reduced pressure to give an oil, which is taken up with ethylacetate. Silica gel is added to the solution and the mixture is stirredfor 15 minutes. It is filtered and the solvent is evaporated off underreduced pressure to give 6.3 g of the title compound.

15d/1-[2-(Biphenyl-4-yl)-2-methylpropyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine

The product of the previous step is dissolved in 70 ml of anhydroustetrahydrofuran. The solution is heated to the reflux point and asolution of 3.7 ml (0.039 mol) of borane/dimethylsulfide in 45 ml ofanhydrous tetrahydrofuran is added dropwise. The mixture is refluxed for4 hours and then cooled to 10-15° C. and 15 ml of methanol are addedcautiously. The mixture is stirred for 15 min at room temperature andthen for 30 min under reflux. The solvent is evaporated off underreduced pressure, the residue is taken up with 15 ml of water, ammoniumhydroxide is added until the pH is basic, and the mixture is extractedwith ethyl acetate. The organic phase is washed with water and driedover sodium sulfate and the solvent is evaporated off under reducedpressure to give the title compound, which is crystallized from 50 ml ofmethanol. M.p.=270-272° C.

15e/1-[2-(Biphenyl-4-yl)-2-methylpropyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

1.7 g (0.0035 mol) of the product of the previous step, 14.6 ml ofglacial acetic acid and 4.4 ml of 96% sulfuric acid are mixed. Themixture is refluxed for two hours and then poured into a water/icemixture. Sodium hydroxide is added until the pH is basic, the mixture isextracted with ethyl acetate, the extract is dried over sodium sulfateand the solvent is evaporated off under reduced pressure. Thehydrochloride is prepared with a saturated solution of hydrochloric acidin isopropanol. M.p.=238-240° C.

EXAMPLE 16

1-[2-(4-Phenoxyphenyl)-2-ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride16a/1-Bromo-2-(4-phenoxyphenyl)ethane

A mixture of 3.31 g (0.038 mol) of bromoacetyl bromide, 50 ml ofmethylene chloride and 5 g (0.029 mol) of diphenyl ether is cooled to0-5° C. and 4.42 ml (0.033 mol) of aluminum chloride are added. Themixture is stirred at room temperature for 4 hours. It is poured intoa-water/ice mixture, the two phases are separated and the organic phaseis washed with 1 N hydrochloric acid and with water. The organic phaseis dried over sodium sulfate and the solvent is evaporated off underreduced pressure. The residue is purified by chromatography on a silicagel column using a 7/3 cyclohexane/ethyl acetate mixture as the eluent.The fraction of the medium corresponding to 3.2 g of2-(4-phenoxyphenyl)acetyl bromide is isolated. The resulting oil ismixed with 5.9 ml (0.077 mol) of trifluoroacetic acid and 7.7 ml (0.048mol) of triethylsilane. The mixture is heated at 80° C. for 4 hours andthe residue is taken up with an ethyl ether/sodium bicarbonate mixture.The two phases are separated, the organic phase is dried over sodiumsulfate and the solvent is evaporated off under reduced pressure to give7 g of the title compound.

16b/1-[2-(4-Phenoxyphenyl)-2-ethyl]-4-(3-trifluoro -methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

A mixture of 2.63 g (0.010 mol) of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine, 80 ml of butanol, 3.5 g (0.025mol) of anhydrous potassium carbonate chips and 3.05 g (0.011 mol) ofthe product of the previous step is refluxed for 5 hours. The salts arefiltered off, the solvent is evaporated off under reduced pressure, theresidue is taken up with ethyl acetate, the mixture is washed with waterand dried over sodium sulfate and the solvent is evaporated off underreduced pressure. The crude product is purified by chromatography on asilica gel column using a 3/7 ethyl acetate/cyclohexane mixture as theeluent. The product of Rf≈0.5 is isolated. The hydrochloride is preparedwith a saturated solution of hydrochloric acid in isopropanol.M.p.=196-198° C.

EXAMPLE 17

1-[2-(4-Benzylphenyl)-2-ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride17a/1-Bromo-2-(4-benzylphenyl)ethane

A mixture of 2.7 g (0.030 mol) of bromoacetyl bromide, 54 ml ofmethylene chloride and 4 g (0.0238 mol) of diphenylmethane is cooled to0-5° C. and 3.7 ml (0.0274 mol) of aluminum chloride are added. Themixture is stirred at room temperature for 4 hours. It is poured into awater/ice mixture and the two phases are separated. The organic phase isdried over sodium sulfate and the solvent is evaporated off underreduced pressure. The residue is taken up with isopropyl ether, themixture is stirred and the precipitate formed is filtered off. 4.5 g of2-(4-benzylphenyl)acetyl bromide are isolated. The resulting product ismixed with 8 ml of trifluoroacetic acid and 4.57 ml (0.048 mol) oftriethylsilane. The mixture is heated at 80° C. for 4 hours and theresidue is taken up with an ethyl ether/sodium bicarbonate mixture. Thetwo phases are separated, the organic phase is dried over sodium sulfateand the solvent is evaporated off under reduced pressure to give 6.5 gof the title compound, which is purified by chromatography on a silicagel column using a 9/1 cyclohexane/ethyl acetate mixture as the eluent.The first eluted fraction, which corresponds to the title compound, isisolated.

17b/1-[2-(4-Benzylphenyl)-2-ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

A mixture of 2.6 g (0.0098 mol) of 4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine, 80 ml of butanol, 3.4 g(0.0246 mol) of anhydrous potassium carbonate chips and 3 g of theproduct of the previous step is refluxed for 5 hours. The salts arefiltered off, the solvent is evaporated off under reduced pressure, theresidue is taken up with ethyl acetate, the mixture is washed with waterand dried over sodium sulfate and the solvent is evaporated off underreduced pressure. The crude product is purified by chromatography on asilica gel column using a 3/7 ethyl acetate/cyclohexane mixture as theeluent. 2 g of base are isolated. The hydrochloride is prepared with asaturated solution of hydrochloric acid in isopropanol to give the titlecompound, which is crystallized from acetone. M.p.=169-172° C.

EXAMPLE 18

1-[2-(4-n-Butylphenyl)ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine oxalate18a/1-Bromo-2-(4-n-butylphenyl)ethane

2.5 g of the title compound are obtained by following the proceduredescribed in Example 8a but using 4.7 ml (0.030 mol) of n-butylbenzeneinstead of 3-chlorobiphenyl. Thin layer chromatography (eluent:cyclohexane): Rf=0.4.

18b/1-[2-(4-n-Butylphenyl)ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine oxalate

Crude 1-[2-(4-n-butylphenyl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine is obtained by following theprocedure described in Example 8b but using the compound of step 18a.This is purified by chromatography on a silica gel column using a 1/1ethyl acetate/cyclohexane mixture as the eluent. The oxalate is preparedwith oxalic acid in acetone. The resulting product is crystallized fromisopropanol to give 1.18 g of the title compound. M.p.=162-165° C.

EXAMPLE 19

1-[2-(Biphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridineand its hydrochloride 19a/Ethyl biphenyl-4-ylacetate

The title compound is obtained by following the procedure described inExample 1a using biphenyl-4-ylacetic acid instead of2-(4-isobutylphenyl)propionic acid.

19b/Biphenyl-4-ylethyl alcohol

The title compound is obtained by following the procedure described inExample 1b using the product of step 19a. M.p.=75-30° C.

19c/2-(Biphenyl-4-yl)ethyl methanesulfonate

The title compound is obtained by following the procedure described inExample 1c using the product of step 19b. M.p.=75-77° C.

19d/1-[2-(Biphenyl-4-yl)ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine and its hydrochloride

A mixture of 8.3 g (0.03 mol) of the product of the previous step, 100ml of isopropanol, 12.8 ml (0.0915 mol) of triethylamine and 7.91 g(0.03 mol) of 4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine isrefluxed for 8 hours. The solvent is evaporated off under reducedpressure and the residue is taken up with 70 ml of ethyl acetate. Themixture is washed twice with water and dried over sodium sulfate and thesolvent is evaporated off under reduced pressure to give1-[2-(biphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine,which is crystallized from 30 ml of isopropanol. M.p.=114-116° C.

The hydrochloride is prepared with a saturated solution of hydrochloricacid in isopropanol to give the title compound, which is crystallizedfrom 95% ethanol. M.p.=262-263° C.

EXAMPLE 20

1-[2-(4-n-Butoxyphenyl)ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride20a/1-[2-(4-Hydroxyphenyl)ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine and its hydrochloride

A mixture of 5.6 g (0.0211 mol) of 4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine, 7.3 g (0.0528 mol) ofpotassium carbonate, 112 ml of amyl alcohol and 3.3 g (0.0211 mol) of4-hydroxyphenethyl chloride is refluxed for 5 hours. Any salts arefiltered off, the solvent is evaporated off under reduced pressure, theresidue is taken up with ethyl acetate, the mixture is washed withwater, the organic phase is dried over sodium sulfate and the solvent isevaporated off under reduced pressure. The hydrochloride is preparedwith a saturated solution of hydrochloric acid in isopropanol to give 3g of the title compound. M.p.=220-222° C.

20b/1-[2-(4-n-Butoxyphenyl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

A mixture of 1 g (0.0029 mol) of the compound of the previous step inthe form of the base, 15 ml of DMSO and 150 mg (0.0038 mol) of 60%sodium hydride is stirred for 2 hours at room temperature. 0.4 ml(0.0038 mol) of 1-bromobutane and 150 mg (0.001 mol) of potassium iodideare added to the reaction mixture, which is stirred for a further twohours at room temperature. It is poured into a water/ice mixture andextracted with ethyl acetate, the organic phase is dried over sodiumsulfate and the solvent is evaporated off under reduced pressure. Thehydrochloride is prepared with a saturated solution of hydrochloric acidin isopropanol to give 500 mg of the title compound. M.p.=212-214° C.

EXAMPLE 21

1-[2-(4-(3-Ethoxycarbonylpropoxy)phenyl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

The procedure described in Example 20b is followed using ethyl4-bromobutyrate instead of 1-bromobutane. This gives the title compound,which is crystallized from isopropanol. M.p.=204-205° C.

    ______________________________________                                        Elemental analysis                                                                          % C         % H    % N                                          ______________________________________                                        calculated    62.71       6.27   2.81                                           found 62.69 6.34 2.80                                                       ______________________________________                                    

EXAMPLE 22

1-[2-(Biphenyl-4-yl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine22a/(1-Benzyl-1,2,3,6-tetrahydropyrid-4-yl)tributyl-stannane

A mixture of 15.85 g (0.0837 mol) of 1-benzyl-4-piperidone in 140 ml ofanhydrous dimethoxyethane and 25 g (0.0837 mol) of trisilidrazine in 140ml of anhydrous dimethoxyethane is stirred at room temperature for 3hours. The solvent is evaporated off under reduced pressure. The residueis taken up with 420 ml of anhydrous hexane, and 420 ml of anhydroustetramethylethylenediamine are added. The mixture is cooled to -78° C.and 156 ml of n-butyllithium (0.25 mol) (1.6 M solution in hexane) areadded dropwise. After about 30 minutes the temperature is allowed torise to 0° C. and the mixture is stirred for 15 minutes. 45 ml (0.167mol) of tributylstannane chloride are then added to the reactionmixture. After 1 hour a water/ice mixture is added extremely cautiously.The reaction medium is extracted with ethyl ether, the organic phase iswashed with water and dried over sodium sulfate and the solvent isevaporated off under reduced pressure. This gives 70 g of crude product,which is purified by chromatography on a silica gel column using a 95/5cyclohexane/ethyl acetate mixture as the eluent to give the titlecompound in the form of an oil.

¹ H NMR (CDCl₃)-δ(ppm): 0.84 (9H; m: CH₃); 1.19-1.58 (18H; m: CH₂-chain); 2.31 (2H; m); 2.53 (2H; m); 3.02 (2H; m); 3.56 (2H; s: benzylmethylene); 5.76 (1H; m*); 7.14-7.18 (5H; m: arom.).

satellite bands: ³ J_(cis) (¹ H-¹¹⁷ Sn) and ³ J_(cis) (¹ H-¹¹⁹ Sn).

22b/1-Benzyl-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine

18.5 g (0.04 mol) of the compound of the previous step are dissolved in200 ml of anhydrous dimethylformamide under a nitrogen atmosphere. 11.8g (0.08 mol) of 2,6-dichloropyridine, 0.64 g of Pd(II)(Ph₃ P)₂ Cl₂, 4.38g (0.04 mol) of tetramethylammonium chloride and 2.76 g (0.02 mol) ofpotassium carbonate are added to the solution. The mixture is heated at110° C. for 6 hours and then poured into 100 ml of 5% sulfuric acidsolution. It is extracted with ethyl ether, ammonium hydroxide is addedto the aqueous phase until the pH is basic, and the mixture is extractedwith ethyl acetate. The combined organic phases are dried over sodiumsulfate and the solvent is evaporated off under reduced pressure. Theresidue is purified by chromatography on a silica gel column using a 1/1cyclohexane/ethyl acetate mixture as the eluent to give the titlecompound. M.p.=100-102° C.

22c/4-(6-Chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine hydrochloride

A solution of 7.0 g (0.024 mol) of the compound of the previous step in110 ml of dichloroethane is cooled to 0-5° C. and 5.8 ml (0.054 mol) ofchloroethylchloroformate are added. The mixture is stirred for 5 minutesand then refluxed for 1.5 hours. The solvent is evaporated off underreduced pressure, the residue is taken up with 100 ml of methanol andthe mixture is refluxed for 1 hour. The solvent is evaporated off, theresidue is taken up with isopropanol and the solid is filtered off togive the title compound, which is crystallized from 90% ethanol.M.p.=305-307° C.

22d/1-[2-(Biphenyl-4-yl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine

A mixture of 1.35, g (0.0053 mol) of 4-(2-bromo-ethyl)biphenyl, 25 ml ofbutanol, 1.72 g (0.0125 mol) of anhydrous potassium carbonate chips and1.16 g (0.005 mol) of the product of the previous step is refluxed for 6hours. The solvent is evaporated off under reduced pressure, the residueis taken up with ethyl acetate, the mixture is washed with water anddried over sodium sulfate and the solvent is evaporated off underreduced pressure. The residue is taken up with 30 ml of isopropyl etherand the precipitate formed is filtered off to give the title compound,which is recrystallized from isopropanol. M.p.=135-136° C.

EXAMPLE 23

1-[2-(2,3'-Dichlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride 23a/Ethyl(3-chloro-4-trifluoromethylsulfonylphenyl) acetate

Gaseous hydrochloric acid is bubbled into a solution of 5 g (27 mmol) of(3-chloro-4-hydroxyphenyl)acetic acid in 60 ml of ethanol, with coolingin an ice bath for one hour, and the mixture is then refluxed for 5hours. The solvent is evaporated off, the residue is taken up withsaturated aqueous sodium bicarbonate solution and the mixture isextracted with ethyl acetate. The extract is filtered, the organic phaseis dried over sodium sulfate and the solvent is evaporated off underreduced pressure. The crude product is purified by chromatography on asilica gel column using a 7/3 cyclohexane/ethyl acetate mixture as theeluent to give ethyl 3-chloro-4-hydroxyphenyl acetate.

4 g (18.6 mmol) of this compound are dissolved in 14 ml of pyridine, and3.36 ml (20 mmol) of triflic anhydride are added dropwise under anitrogen atmosphere, the temperature being maintained at 0° C. for 1hour. The mixture is poured into ice and extracted with ethyl acetate.The organic phase is dried over sodium sulfate and filtered and thesolvent is evaporated off under reduced pressure. The crude product ispurified by chromatography on a silica gel column using a 9/1cyclohexane/ethyl acetate mixture as the eluent to give the titlecompound.

23b/Ethyl (2,3'-dichlorobiphenyl-4-yl)acetate

A mixture of 4.9 g (14 mmol) of the product of the previous step, 2.45 g(16 mmol) of 3-chlorobenzeneboronic acid, 63 mg (0.28 mmol) of palladiumacetate, 4.84 g (35 mmol) of potassium carbonate and 4.5 g (14 mmol) oftetrabutylammonium bromide in 19 ml of water is stirred at 70° C. for 1hour. It is allowed to cool and extracted with ethyl acetate. Theorganic phase is dried over sodium sulfate and filtered and the solventis evaporated off under reduced pressure. The crude reaction product ispurified by chromatography on a silica gel column using a 9/1cyclohexane/ethyl acetate mixture as the eluent to give the titlecompound in the form of an oil.

23c/(2,3 '-Dichlorobiphenyl-4-yl) acetic acid

A mixture of the product obtained in the previous step and 1.57 g (28mmol) of potassium hydroxide in 39 ml of methanol is heated at 80° C.for 2 hours. The solvent is evaporated off under reduced pressure andthe residue is washed with 1 N hydrochloric acid solution and extractedwith methylene chloride. The organic phase is dried over sodium sulfateand filtered and the solvent is evaporated off under reduced pressure.The crude product is treated with hexane to give a white precipitate.This is filtered off and crystallized from a hexane/ethyl acetatemixture to give 1.4 g of the title product. M.p.=92-94° C.

23d/1-[(2,3'-Dichlorobiphenyl-4-yl)acetyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine

A mixture of 1.2 g (4.3 mmol) of the product of the previous step, 1.2 g(4.3 mmol) of 4-hydroxy-4-(3-trifluoromethylphenyl)piperidine, 17.2 mlof methylene chloride, 1.54 ml (11 mmol) of triethylamine and 1.9 g (4.3mmol) of BOP is stirred at room temperature for 24 hours. It is pouredinto water and extracted with methylene chloride and the organic phaseis washed with 1 N hydrochloric acid solution, with water, with 1 Nsodium hydroxide solution and again with water. The organic phase isdried over sodium sulfate and filtered and the solvent is evaporated offunder reduced pressure. The crude product is purified by chromatographyon a silica gel column using a 1/1 cyclohexane/ethyl acetate mixture asthe eluent to give the title product in the form of a white solid.M.p.=154-155° C.

23e/1-[2-(2,3'-Dichlorobiphenyl-4-yl)ethyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine

1.6 g (3.15 mmol) of the compound of the previous step in 17 ml oftetrahydrofuran are heated to the reflux point and 0.92 ml (9.3 mmol) ofborane/dimethyl sulfide in 12 ml of tetrahydrofuran is added, refluxbeing maintained for 4 hours. The solution is cooled to 0° C., 15 ml ofmethanol are added and the mixture is stirred for 30 minutes underreflux. The solvent is evaporated off under reduced pressure, theresidue is taken up with water (15 ml), concentrated ammonium hydroxideis added until the pH is basic, the mixture is extracted with ethylacetate, the organic phase is washed with water and dried over sodiumsulfate and the solvent is evaporated off under reduced pressure. Theproduct is purified by chromatography on a silica gel column using a 1/1cyclohexane/ethyl acetate mixture as the eluent to give 1.2 g of thetitle product in the form of an oil.

23f/1-[2-(2,3'-Dichlorobiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

1.2 g (2.43 mmol) of the compound of the previous step, 12.7 ml ofglacial acetic acid and 3 ml of 96% sulfuric acid are heated at 100° C.for 1 hour. The mixture is poured into a water/ice mixture, 20% sodiumhydroxide solution is added until the pH is basic, the resulting mixtureis extracted with ethyl acetate, the organic phase is washed with waterand dried over sodium sulfate and the solvent is evaporated off underreduced pressure. The product is purified by chromatography on a silicagel column using a 7/3 cyclohexane/ethyl acetate mixture as the eluent.The hydrochloride of the resulting product is prepared with a saturatedsolution of hydrochloric acid in isopropanol.

A white solid is obtained. M.p.=204-206° C.

EXAMPLE 24

1-[2-(3-Chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride 24a/Ethyl(2-chloro-4-trifluoromethylsulfonylphenyl) acetate

The title compound is obtained by following the procedure described inExample 23a but using (2-chloro-4-hydroxyphenyl)acetic acid, preparedaccording to Preparation 4, instead of (3-chloro-4-hydroxyphenyl)aceticacid.

24b/Ethyl (3-chlorobiphenyl-4-yl)acetate

The title compound is obtained by following the procedure described inExample 23b but using the product of the previous step instead of theproduct of step 23a and benzeneboronic acid instead of3-chlorobenzeneboronic acid.

24c/(3-Chlorobiphenyl-4-yl)acetic acid

The title compound is obtained by following the procedure described inExample 23c but using the ester of the previous step.

24d/1-[(3-Chlorobiphenyl-4-yl)acetyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine

The title compound is obtained by following the procedure described inExample 23d but using the product of the previous step instead of theproduct of step 23c.

24e/1-[2-(3-Chlorobiphenyl-4-yl)ethyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine

The title compound is obtained by following the procedure described inExample 23e but using the product of the previous step instead of theproduct of step 23d.

24f/1-[2-(3-Chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

The title compound is obtained by following the procedure described inExample 23f but using the product of the previous step instead of theproduct of step 23e. M.p.=227° C.

EXAMPLE 25

1-[2-(3',5'-Dichlorobiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride25a/2-(31,5'-Dichlorobiphenyl-4-yl)ethanol

The title compound is obtained by following the procedure described inExample 23b but using 2-(p-bromophenyl)ethanol instead of ethyl(3-chloro-4-trifluoromethyl-sulfonylphenyl)acetate and3,5-dichlorobenzeneboronic acid instead of 3-chlorobenzeneboronic acid.

25b/2-(3',5'-Dichlorobiphenyl-4-yl)ethyl methanesulfonate

The title compound is obtained by following the procedure described inExample 1c but using the product of the previous step instead of2-(4-isobutylphenyl)propyl alcohol.

25c/1-[2-(3',5'-Dichlorobiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

The title compound is obtained by following the procedure described inExample 1d but using the product of the previous step instead of2-(4-isobutylphenyl)propyl methanesulfonate. M.p.=200-202° C.

EXAMPLE 26

1-[2-(2',4'-Dichlorobiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

The title compound is obtained by following the procedure described inExample 25 but using 2,4-dichlorobenzeneboronic acid instead of3,5-dichlorobenzeneboronic acid. M.p.=204-206° C.

EXAMPLE 27

1-[2-(2-Chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride27a/(2-Chlorobiphenyl-4-yl) acetic acid

By following the procedure described in Example 23b but usingbenzeneboronic acid instead of 3-chlorobenzeneboronic acid, the titlecompound is obtained in the form of a solid, which is crystallized fromethyl acetate. M.p.=103-105° C.

27b/1-[(2-Chlorobiphenyl-4-yl)acetyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine

The title compound is obtained by following the procedure described inExample 23d but using the compound of the previous step instead of(2,3'-dichlorobiphenyl-4-yl)acetic acid. M.p.=46-490C.

27c/1-[2-(2-Chlorobiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

The title compound is obtained by following the procedure described inExamples 23e and 23f but using the product of the previous step insteadof1-[(2,3'-dichlorobiphenyl-4-yl)acetyl]-4-hydroxy-4-(3-trifluoromethylphenyl)piperidine.M.p.=210-212° C.

EXAMPLE 28

1-[2-(3'-Chlorobiphenyl-4-yl)-2-methylpropyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride 28a/Ethyl 2-(4-bromophenyl)-2-methylpropionate

7.5 g (31 mmol) of ethyl 4-bromophenylacetate are dissolved in 120 ml ofDMF, and 2.5 g of sodium hydride (60% dispersion in oil) are addedslowly. The mixture is stirred at room temperature for 30 minutes andthen cooled to 100° C., 4.1 ml (61 mmol) of methyl iodide are added andthe mixture is stirred at room temperature for 4 hours. It is pouredinto a water/ice mixture and extracted with ethyl acetate, the organicphase is dried over sodium sulfate and filtered and the solvent isevaporated off under reduced pressure. The crude product is purified bychromatography on a silica gel column using a 95/5 cyclohexane/ethylacetate mixture as the eluent to give the title compound.

28b/2-(3'-Chlorobiphenyl-4-yl) -2-methylpropionic acid

A mixture of 2.18 g (8 mmol) of the product of the previous step, 1.38 g(8.8 mmol) of 3-chlorobenzeneboronic acid, 2.16 g (20 mmol) of potassiumbicarbonate, 2.58 g (8 mmol) of tetrabutylammonium bromide and 40 mg ofpalladium acetate in 11 ml of water is heated at 70° C. for 3 hoursunder an argon atmosphere. After cooling, it is extracted with ethylacetate. The organic phase is dried over sodium sulfate and filtered andthe solvent is evaporated off under reduced pressure.

The crude reaction product is purified by chromatography on a silica gelcolumn using a 9/1 cyclohexane/ethyl acetate mixture as the eluent togive 1.85 g of the ethyl ester of the title acid. This product is mixedwith 0.7 g of potassium hydroxide in 14 ml of methanol and the mixtureis heated at 80° C. for 3 hours. The solvent is evaporated off and theresidue is poured into water. The mixture is acidified with 1 Nhydrochloric acid solution. It is extracted with methylene chloride, theorganic phase is dried over sodium sulfate and filtered and the solventis evaporated off under reduced pressure. The solid obtained iscrystallized from a hexane/ethyl acetate mixture to give 1 g of thetitle compound in the form of a white solid. M.p.=145-146° C.

28c/1-[2-(3'-Chlorobiphenyl-4-yl)-2-methylpropyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

The title compound is obtained by following the procedure described inExamples 23d, 23e and 23f but using the compound of the previous stepinstead of (2,3'-dichlorobiphenyl-4-yl)acetic acid. M.p.=215-217° C.

EXAMPLE 29

1-[2-(2-Fluorobiphenyl-4-yl)propyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

The title compound is obtained by following the procedure described inExamples 23d, 23e and 23f but using flurbiprofen instead of(2,3'-dichlorobiphenyl-4-yl)acetic acid. M.p.=181-183° C. (free base);m.p.=204-206° C. (hydrochloride).

EXAMPLE 30

1-[2-(4-Methoxybiphenyl-3-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride and1-[2-(4'-methoxybiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine

11.5 g (0.0652 mol) of 4-methoxybiphenyl, 50 ml of dichloroethane and5.42 g (0.0625 mol) of bromoacetyl bromide are mixed. The mixture iscooled to -10° C. and 9.3 g (0.070 mol) of aluminum trichloride areadded. The mixture is stirred at -10° C. for 2 hours and acidified with1 N hydrochloric acid solution, the two phases are separated and theaqueous phase is extracted with ethyl acetate. The combined organicphases are dried over sodium sulfate, the solvent is evaporated offunder reduced pressure and the crude product is purified bychromatography on a silica gel column using a 9/1 cyclohexane/ethylacetate mixture as the eluent. A fraction of Rf≈0.3, consisting of a75:25 mixture of the 3-bromoacetyl-4-methoxybiphenyl and4'-bromoacetyl-4-methoxybiphenyl isomers, is isolated. 5.8 g (0.019 mol)of the above isomer mixture in 11.6 ml of trifluoroacetic acid and 5.8ml of triethylsilane are refluxed for 3 hours. The mixture is pouredinto ice, 1 N sodium hydroxide solution is added until the pH is basic,and the mixture is extracted with ethyl acetate. The organic phase isdried over sodium sulfate and the solvent is evaporated off underreduced pressure. The residue is taken up with 160 ml of butanol, and5.1 g (0.019 mol) of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine and 5.9 g (0.0427mol) of potassium carbonate are added. The mixture is refluxed for 6hours, the salts formed are filtered off and the solvent is evaporatedoff under reduced pressure. The residue is taken up with ethyl acetate,the mixture is washed with water, the organic phase is dried over sodiumsulfate and the solvent is evaporated off under reduced pressure. Theresidue is purified by chromatography on a silica gel column using a 7/3cyclohexane/ethyl acetate mixture as the eluent. The fraction of Rf≈0.5is isolated (thin layer chromatography; eluent: cyclohexane/ethylacetate=1/1). The product with the slightly higher Rf corresponds to1-[2-(4-methoxybiphenyl-3-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine,the hydrochloride of which is prepared with a saturated solution ofhydrochloric acid in ethyl ether. 0.9 g is obtained. M.p.=185-187° C.(crystallized from acetone).

The product with the slightly lower Rf, corresponding to1-[2-(4'-methoxybiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine, is isolated from isopropylether in the form of a solid. M.p.=120-123° C.

EXAMPLE 31

1-[2-(4'-Hydroxybiphenyl-4-yl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride

0.5 g (1.14 mmol) of1-[2-(4'-methoxybiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine,prepared according to Example 30, is dissolved in 3.5 ml of 33%hydrobromic acid in acetic acid and the solution is refluxed for 3.5hours. It is poured into ice and concentrated ammonium hydroxidesolution is added to the mixture, which is extracted with ethyl acetate.The organic phase is washed with water and dried and the solvent isevaporated off under reduced pressure. The residue is purified bychromatography on a silica gel column using a 7/3 cyclohexane/ethylacetate mixture as the eluent. The hydrochloride is prepared with asaturated solution of hydrochloric acid in ethyl ether to give 0.43 g ofthe title product, which is crystallized from 95% ethanol. M.p.=248-254°C.

EXAMPLE 32

1-[2-(4'-Ethoxycarbonylbutoxybiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

A mixture of 400 mg (0.9 mmol) of the product of Example 31 (free base),5 ml of DMSO and 49 mg of 60% sodium hydride is stirred at roomtemperature for 2 hours. 46 mg of potassium iodide and 0.17 ml (1 mmol)of ethyl 1-bromobutyrate are added. The mixture is stirred at roomtemperature for 2 hours, poured into water and extracted with ethylacetate. The organic phase is washed with water and dried over sodiumsulfate and the solvent is evaporated off under reduced pressure. Theresidue is purified by chromatography on a silica gel column using an8/2 cyclohexane/ethyl acetate mixture as the eluent. The hydrochlorideis prepared with a saturated solution of hydrochloric acid in an ethylether/isopropanol mixture to give the title compound. M.p.=242-247° C.

EXAMPLE 33

1-[2-(Biphenyl-3-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride 33a/2-(Biphenyl-3-yl) ethanol

The title compound is obtained by following the procedure described inExample 23b but using 3-bromophenethyl alcohol instead of(3-chloro-4-trifluoromethylsulfonylphenyl)acetic acid ester andbenzeneboronic acid instead of 3-chlorobenzeneboronic acid. M.p.=58-60°C.

33b/2-(Biphenyl-3-yl)ethyl p-toluenesulfonate

0.7 g (3.5 mmol) of the product of the previous step and 1 g (5.2 mmol)of tosyl chloride in 5 ml of pyridine are stirred at room temperatureovernight. The mixture is poured into 1 N hydrochloric acid solution andextracted with ethyl acetate. The organic phase is washed with 3 Msodium hydroxide solution. It is dried over sodium sulfate andevaporated under reduced pressure. The residue is purified bychromatography on a silica gel column using a 9/1 and then 8/2cyclohexane/ethyl acetate mixture as the eluent to give the titlecompound in the form of an oil.

33c/1-[2-(Biphenyl-3-yl)ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine hydrochloride

The title compound is obtained by following the procedure described inExample 1d but using the product of the previous step instead of2-(4-isobutylphenyl)propyl methanesulfonate. M.p.=191-192° C.

EXAMPLE 34

1-[2-(3'-Chloro-4'-fluorobiphenyl-4-yl)ethyl]-4-(3-tri-fluoromethylphenyl)-1,2,3,6-tetrahydropyridine hydrochloride34a/2-(31-Chloro-4'-fluorobiphenyl-4-yl)ethanol

The title compound is obtained by following the procedure described inExample 23b but using 2-(p-bromophenyl)ethanol instead of ethyl(3-chloro-4-trifluoro -methylsulfonylphenyl)acetate and3-chloro-4-fluorobenzeneboronic acid instead of 3-chlorobenzeneboronicacid.

34b/2-(3'-Chloro-4'-fluorobiphenyl-4-yl)ethyl methanesulfonate

The title compound is obtained by following the procedure described inExample 1c but using the product of the previous step instead of2-(4-isobutylphenyl)propyl alcohol.

34c/1-[2-(3'-Chloro-4'-fluorobiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

The title compound is obtained by following the procedure described inExample 1d but using the product of the previous step instead of2-(4-isobutylphenyl)propyl methanesulfonate. M.p.=218-22° C.

EXAMPLE 35

1-[2-(2'-Trifluoromethylbiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride 35a/2-(4-Bromophenyl)-2,2-dimethoxyethane

A mixture of 2 g (0.01 mol) of 4-bromoacetophenone, 5.6 ml oftrimethylorthoformate, 5.6 ml of methanol and 0.67 g of Amberlite® IR120 is refluxed for 3 hours. After cooling, it is filtered on Celite andthe filtered solution is evaporated to give 2.4 g of the title productin the form of an oil.

35b/2,2-Dimethoxy-2-(2'-trifluoromethylbiphenyl-4-yl) ethane

The title compound is obtained by following the procedure described inExample 23b but using the product of the previous step instead of ethyl(2,3'-dichlorobiphenyl-4-yl)acetate and2-trifluoromethylphenylbenzeneboronic acid instead of3-chlorobenzeneboronic acid.

35c/4-(2-Trifluoromethylphenyl)acetophenone

A solution of 4 ml of trifluoroacetic acid and 4 ml of water is added at0° C. to a solution of 4.6 g (0.0105 mol) of the product of the previousstep in 4 ml of methylene chloride. The mixture is stirred at roomtemperature for 2 hours, poured into water and extracted with methylenechloride. The organic phase is dried and filtered and the solvent isevaporated off under reduced pressure. The crude product is purified bychromatography on a silica gel column using a 9/1 cyclohexane/ethylacetate mixture as the eluent to give 1.97 g of the title product.

35d/α-Bromo-4-(2-trifluoromethylphenyl)acetophenone

0.38 ml (7.5 mmol) of bromine is added dropwise at a temperature of 0°C. to a solution of 1.97 g (7.5 mmol) of the product of the previousstep in 5.4 ml of methanol. The 5 mixture is stirred at room temperaturefor 3 hours, the solvent is evaporated off, the residue is taken up withwater and the mixture is extracted with ethyl acetate. The organic phaseis dried over sodium sulfate and filtered and the solvent is evaporatedoff under reduced pressure to give 2.3 g of the title product.

35e/1-Bromo-2-(2'-trifluoromethylbiphenyl-4-yl)ethane

1.2 g (3.5 mmol) of the product of the previous step, 4.4 ml oftrifluoroacetic acid and 2.3 ml of triethylsilane are mixed and themixture is refluxed for 3 hours. It is then poured into a mixtureconsisting of concentrated sodium hydroxide solution and ice, thereaction medium is extracted with ethyl acetate, the organic phase isdried over sodium sulfate and the solvent is evaporated off underreduced pressure to give the title compound.

35f/1-[2-(2'-Trifluoromethylbiphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridinehydrochloride

The title compound is obtained by following the procedure described inExample 1d but using the product of the previous step instead of2-(4-isobutylphenyl)propyl methanesulfonate. M.p.=176-178° C.

EXAMPLE 36

1-[2-(3,4-Diisobutylphenyl)ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine oxalate 36a/1,2-Diisobutylbenzene

A solution of 9.4 g (0.07 mol) of 1,2-diphthalaldehyde in 30 ml of THFis added dropwise under a nitrogen atmosphere to a 2 M solution ofisopropylmagnesium chloride in THF. The mixture is then stirred at roomtemperature for 2 hours and poured into saturated ammonium chloridesolution, the THF is evaporated off under reduced pressure and theresidue is extracted with ethyl ether. The organic phase is dried oversodium sulfate and the solvent is evaporated off under reduced pressure.The residue is purified by chromatography on a silica gel column using a7/3 cyclohexane/ethyl acetate mixture as the eluent. The resulting diolis dissolved in 110 ml of absolute ethanol, and 5 ml of 96% sulfuricacid and 0.67 g of 10% Pd/C are added. The mixture is hydrogenated atatmospheric pressure and room temperature. After the theoretical amountof hydrogen has been consumed (about 7 hours), the catalyst is filteredoff, the solvent is evaporated off, the residue is taken up with ethylacetate, the mixture is washed with aqueous bicarbonate solution andthen with water, the organic phase is dried and the solvent isevaporated off under reduced pressure to give 3.9 g of the titlecompound in the form of an oil.

36b/1-Bromo-2-(3,4-diisobutylphenyl)ethane

The title compound is obtained by following the procedure described inExample 4a but using the product of the previous step instead ofisobutylbenzene.

36c/1-[2-(3,4-Diisobutylphenyl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine oxalate

The title compound is obtained by following the procedure described inExample 4b but using the product of the previous step instead of1-bromo-2-(4-isobutylphenyl)ethane and treating the resulting base withoxalic acid instead of hydrochloric acid. M.p.=175-178° C.

EXAMPLE 37

1-[2-(3,4-Dipropylphenyl)ethyl]-4-(3-trifluoromethyl-phenyl)-1,2,3,6-tetrahydropyridine oxalate 37a/1,2-Dipropylbenzene

The title compound is obtained by following the procedure described inExample 36a but using 1,2-dicarboxyaldehyde instead of1,2-diphthalaldehyde.

37b/1-Bromo-2-(3,4-dipropylphenyl)ethane

The title compound is obtained by following the procedure described inExample 36b but using the product of the previous step instead of1,2-diisobutylbenzene.

37c/1-[2-(3,4-Dipropylphenyl)ethyl]-4-(3-trifluoro-methylphenyl)-1,2,3,6-tetrahydropyridine oxalate

The title compound is obtained by following the procedure described inExample 36c but using the product of the previous step instead of1-bromo-2-(3,4-diisopropylphenyl)ethane. M.p. =180-182° C.

EXAMPLE 38

1-[2-(4-Cyclohexylphenyl)ethyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine

The title compound is obtained by following the procedure described inExample 22d but using 1-bromo-2-(4-cyclohexylphenyl)ethane (preparedaccording to Example 19a) instead of 4-(2-bromoethyl)biphenyl.

EXAMPLE 39

1-[2-(4-Isobutylphenyl)propyl]-4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridinehydrochloride

The title compound is obtained by following the procedure described inExample 1d but using 4-(6-chloropyrid-2-yl)-1,2,3,6-tetrahydropyridine(prepared according to Example 22c) instead of4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine. M.p.=185-190° C.

We claim:
 1. A compound of formula (I): ##STR21## in which Y is --CH--or --N--;R₁ is hydrogen, a halogen atom, a CF₃ group, a (C₃ -C₄)alkyl ora (C₁ -C₄)alkoxy group; R₂ is hydrogen, a halogen atom, a hydroxy group,a CF₃ group, a (C₃ -C₄)alkyl or a (C_(1-C) ₄)alkoxy group; R₃ and R₄ areeach hydrogen or a (C₁ -C₃)alkyl group; and X is(a) a (C₃ -C₆)alkylgroup, a (C₃ -C₆)alkoxy group, a (C₃ -C₇)carboxyalkyl group, a (C₁-C₄)alkoxycarbonyl(C₃ -C₆)alkyl group, a (C₃ -C₇)carboxyalkoxy group ora (C₁ -C₄)alkoxycarbonyl(C₃ -C₆)alkoxy group; (b) a (C₃ -C₇)cycloalkylgroup, a (C₃ -C₇)cycloalkoxy group, a (C₃ -C₇)cycloalkylmethyl group, a(C₃ -C₇)cycloalkylamino group or a cyclohexenyl group, it being possiblefor said group to be substituted by a halogen atom, a hydroxyl group, a(C₁ -C₄)alkoxy group, a carboxyl group, a (C₁ -C₄)alkoxycarbonyl group,an amino group or a mono- or di-(C₁ -C₄)alkylamino group; or (c) aphenyl group, a phenoxy group, a phenylamino group, a N-(C₁-C₃)alkylphenylamino group, a phenylmethyl group, a phenylethyl group, aphenylcarbonyl group, a phenylthio group, a phenylsulfonyl group, aphenylsulfinyl group or a styryl group, it being possible for said groupto be monosubstituted or polysubstituted on the phenyl group by ahalogen atom, a CF₃ group, a (C₁ -C₄)alkyl group, a (C₁ -C₄)alkoxygroup, a cyano group, an amino group, a mono- or di-(C₁ -C₄)alkylaminogroup, a (C₁ -C₄)acylamino group, a carboxyl group, a (C₁-C₄)alkoxycarbonyl group, an aminocarbonyl group, a mono- or a di-(C₁-C₄)alkylaminocarbonyl group, an amino (C₁ -C₄)alkyl group, a hydroxy(C₁-C₄)alkyl group or a halogeno(C₁ -C₄)alkyl group; a salt, solvate or aquaternary ammonium salt thereof.
 2. A compound according to claim 1 inwhich X is in the 4-position of the phenyl group.
 3. A process for thepreparation of a compound of formula (I) of claim 1, a salt, solvate ora quaternary ammonium salt thereof, which comprises(a) reacting anaryl-1,2,3,6-tetrahydropyridine of formula (II): ##STR22## in which Yand R₁ are as defined for (I) in claim 1, with a compound of formula(III) ##STR23## in which R₂, R₃, R₄ and X are as defined for (I) inclaim 1 and L is a leaving group; and (b) isolating the resultingcompound of formula (I) and optionally converting it to a salt, solvateor a quaternary ammonium salt thereof.
 4. A process for the preparationof a compound formula (I) of claim 1 in which Y is --CH--, a salt,solvate or a quaternary ammonium salt thereof, which comprises(a)reacting a compound of formula (IV): ##STR24## in which R₁ is as definedfor (I) in claim 1, with a functional derivative of the acid of formula(V): ##STR25## in which R₂, R₃, R₄ and X are as defined for (I) in claim1 (b) reacting the carbonyl group of the resulting compound of formula(VI): ##STR26## (c) dehydrating the resulting intermediate piperidinolof formula (VII): ##STR27## and (d) isolating the resulting compound offormula (I) and optionally converting it to a salt, solvate or aquaternary ammonium salt thereof.
 5. A compound of formula (i):##STR28## in which Y is --CH-- or --N--;R₁ is hydrogen, a halogen atom,a CF₃ group, a (C₃ -C₄)alkyl group or a (C₁ -C₄)alkoxy group; R₂ ishydrogen, a halogen atom, a hydroxyl group, a CF₃ group, a (C₃ -C₄)alkylgroup or a (C₁ -C₄)alkoxy group; R₃ and R₄ are each hydrogen or a (C₁-C₃)alkyl group; and X is(a) a (C₃ -C₆)alkyl group, a (C₃ -C₆)alkoxygroup, a (C₃ -C₇)carboxyalkyl group, a (C₁ -C₄)alkoxycarbonyl(C₃-C₆)alkyl group, a (C₃ -C₇)carboxyalkoxy group, or a (C₁-C₄)alkoxycarbonyl(C₃ -C₆)alkoxy group; (b) a (C₃ -C₇)cycloalkyl group,a (C₃ -C₇)cycloalkoxy group, a (C₃ -C₇)cycloalkylmethyl group, a (C₃-C₇)cycloalkylamino group or a cyclohexenyl group, it being possible forsaid group to be substituted by a halogen atom, a hydroxyl group, a (C₁-C₄)alkoxy group, a carboxyl group, a (C₁ -C₄)alkoxycarbonyl group, anamino group or a mono- or di-(C₁ -C₄)alkylamino group; or (c) a phenylgroup, a phenoxy group, a phenylamino group, a N-(C₁-C₃)alkylphenylamino group, a phenylmethyl group, a phenylethyl group, aphenylcarbonyl group, a phenylthio group, a phenylsulfonyl group, aphenylsulfinyl group or a styryl group, it being possible for said groupto be monosubstituted or polysubstituted on the phenyl group by ahalogen atom, a CF₃ group, a (C₁ -C₄)alkyl group, a (C₁ -C₄)alkoxygroup, a cyano group, an amino group, a mono- or di-(C₁ -C₄)alkylaminogroup, a (C₁ -C₄)acylamino group, a carboxyl group, a (C₁-C₄)alkoxycarbonyl group, an aminocarbonyl group, a mono- or a di-(C₁-C₄)alkylaminocarbonyl group, an amino (C₁ -C₄)alkyl group, a hydroxy(C₁-C₄)alkyl group or a halogeno(C₁ -C₄)alkyl group; W is a methylene groupor a carbonyl group, or a salt thereof.
 6. A process for the preparationof a compound of formula (t'): ##STR29## in which R₂ is hydrogen, ahalogen atom, a hydroxyl group, a CF₃ group, a (C₃ -C₄)alkyl group or a(C₁ -C₄)alkoxy group;R₃ and R₄ are each hydrogen or a (C₁ -C₃)alkylgroup, and X' is a phenyl group optionally monosubstituted orpolysubstituted by a halogen atom, a CF₃ group, a (C₁ -C₄)alkyl group, a(C₁ -C₄)alkoxy group, a cyano group, an amino group, a mono- or di-(C₁-C₄)alkylamino group, a (C₁ -C₄)acylamino group, a carboxyl group, a (C₁-C₄)alkoxycarbonyl group, an aminocarbonyl group, a mono- or a di-(C₁-C₄)aklylaminocarbonyl group, an amino(C₁ -C₄)alkyl group, a hydroxy(C₁-C₄)alkyl group, or a halogeno(C₁ -C₄)alkyl group, G is a carboxyl groupor a group L--CH₂ --, in which L is a leaving group, which processcomprises reacting a compound of formula (w'): ##STR30## in which R₂,R₃, R₄ and G are defined above and L' is a leaving group, with abenzeneboronic acid having a formula X'-B(OH)₂, in which X' is asdefined above, in the presence of a palladium salt, a strong base and aphase transfer agent, in an aqueous medium.
 7. A process according toclaim 6 wherein the leaving group L' is bromine or thetrifluoromethylsulfonyloxy group.
 8. A process according to claim 6wherein the palladium salt used is palladium acetate.
 9. A processaccording to claim 7 wherein the palladium salt used is palladiumacetate.
 10. A process according to claim 6 wherein the strong base usedis an alkali metal hydroxide or a carbonate.
 11. A process according toclaim 7 wherein the strong base used is an alkali metal hydroxide or acarbonate.
 12. A process according to claim 8 wherein the strong baseused is an alkali metal hydroxide or a carbonate.
 13. A processaccording to claim 6 wherein the phase transfer agent is atetraalkylammonium halide.
 14. A process according to claim 7 whereinthe phase transfer agent is a tetraalkylammonium halide.
 15. A processaccording to claim 8 wherein the phase transfer agent is atetraalkylammonium halide.
 16. A process according to claim 10 whereinthe phase transfer agent is a tetraalkylammonium halide.
 17. A processaccording to claim 6 wherein the reaction is carried out at atemperature between 30° C. and the reflux point.
 18. A process accordingto claim 7 wherein the reaction is carried out at a temperature between30° C. and the reflux point.
 19. A process according to claim 8 whereinthe reaction is carried out at a temperature between 30° C. and thereflux point.
 20. A process according to claim 10 wherein the reactionis carried out at a temperature between 30° C. and the reflux point. 21.A process according to claim 13 wherein the reaction is carried out at atemperature between 30° C. and the reflux point.
 22. A process for thepreparation of the compound of formula (t): ##STR31## in which thebenzene group can optionally be substituted and X' is a phenyl groupoptionally monosubstituted or polysubstituted by a halogen atom, a CF₃group, a (C₁ -C₄)alkyl group, a (C₁ -C₄)alkoxy group, a cyano group, anamino group, a mono- or di-(C₁ -C₄)alkylamino group, a (C₁ -C₄)acylaminogroup, a carboxyl group, a (C₁ -C₄)alkoxycarbonyl group, anaminocarbonyl group, a mono- or a di-(C₁ -C₄)alkylaminocarbonyl group,an amino(C₁ -C₄)alkyl group, a hydroxy(C₁ -C₄)alkyl group or ahalogeno(C₁ -C₄) alkyl group, said process comprising reacting acompound of formula (w): ##STR32## in with the benzene group canoptionally be substituted and L' is a leaving group, which abenezeneboronic acid of the formula X'--B(OH)₂, in which X' is asdefined above, in the presence of a palladium salt, a strong base and aphase transfer agent, in an aqueous medium.
 23. A process according toclaim 22 wherein the leaving group L' is bromine or thetrifluoromethylsulfonyloxy group.
 24. A process according to claim 22wherein the palladium salt used is palladium acetate.
 25. A processaccording to claim 22 wherein the strong base used is selected fromalkali metal hydroxides and carbonates.
 26. A process according to claim22 wherein the phase transfer agent is a tetraalkylammonium halide. 27.A process according to claim 22 wherein the reaction is carried out at atemperature between 30° C. and the reflux point.
 28. A process accordingto claim 23 wherein the palladium salt used is palladium acetate.
 29. Aprocess according to claim 23 wherein the strong base used is an alkalimetal hydroxide or a carbonate.
 30. A process according to claim 24wherein the strong base used is an alkali metal hydroxide or acarbonate.
 31. A process according to claim 23 wherein the phasetransfer agent is a tetraalkylammonium halide.
 32. A process accordingto claim 24 wherein the phase transfer agent is a tetraalkylammoniumhalide.
 33. A process according to claim 25 wherein the phase transferagent is a tetraalkylammonium halide.
 34. A process according to claim23 wherein the reaction is carried out at a temperature between 30° C.and the reflux point.
 35. A process according to claim 24 wherein thereaction is carried out at a temperature between 30° C. and the refluxpoint.
 36. A process according to claim 25 wherein the reaction iscarried out at a temperature between 30° C. and the reflux point.
 37. Aprocess according to claim 26 wherein the reaction is carried out at atemperature between 30° C. and the reflux point.
 38. A compound offormula (II'): ##STR33## in which R₁ ' is a halogen atom, a CF₃ group, a(C₃ -C₄)alkyl group or a (C₁ -C₄)alkoxy group or a salt thereof.
 39. Acompound according to claim 1 in which X is a group (c) in which thephenyl group is substituted by 1 to 3 halogen atoms, 1 to 3 CF₃ groups,1 to 3 (C₁ -C₄)alkyl groups, 1 to 3 (C₁ -C₄)alkoxy groups, 1 to 3 cyanogroups, 1 to 3 amino groups, 1 to 3 mono- or di-(C₁ -C₄)alkylaminogroups, 1 to 3 (C₁ -C₄)acylamino groups, 1 to 3 carboxyl groups, 1 to 3(C₁ -C₄)alkoxycarbonyl groups, 1 to 3 aminocarbonyl groups, 1 to 3 mono-or di-(C₁ -C₄)alkylaminocarbonyl groups, 1 to 3 amino(C₁ -C₄)alkylgroups, 1 to 3 hydroxy(C₁ -C₄)alkyl groups or 1 to 3 halogeno(C₁-C₄)alkyl groups.
 40. A compound according to claim 2 in which X is agroup (c) in which the phenyl group is substituted by 1 to 3 halogenatoms, 1 to 3 CF₃ groups, 1 to 3 (C₁ -C₄)alkyl groups, 1 to 3 (C₁-C₄)alkoxy groups, 1 to 3 cyano groups, 1 to 3 amino groups, 1 to 3mono- or di-(C₁ -C₄)alkylamino groups, 1 to 3 (C₁ -C₄)acylamino groups,1 to 3 carboxyl groups, 1 to 3 (C₁ -C₄)alkoxycarbonyl groups, 1 to 3aminocarbonyl groups, 1 to 3 mono- or di-(C₁ -C₄)alkylaminocarbonylgroups, 1 to 3 amino(C₁ -C₄)alkyl groups, 1 to 3 hydroxy(C₁ -C₄)alkylgroups or 1 to 3 halogeno(C₁ -C₄)alkyl groups.
 41. A pharmaceuticalcomposition which contains (i) an effective amount of a compoundaccording to claim 1, a pharmaceutically acceptable salt or solvatethereof or a pharmaceutically acceptable quaternary ammonium saltthereof, and (ii) at least one pharmaceutically acceptable excipient.42. A pharmaceutical composition according to claim 41, which containsfrom 0.5 to 700 mg of said compound.
 43. A pharmaceutical compositionwhich contains (i) an effective amount of a compound according to claim2, a pharmaceutically acceptable salt or solvate thereof or apharmaceutically acceptable quaternary ammonium salt thereof, and (ii)at least one pharmaceutically acceptable excipient.
 44. A pharmaceuticalcomposition according to claim 43, which contains from 0.5 to 700 mg ofsaid compound.
 45. A pharmaceutical composition which contains (i) aneffective amount of a compound according to claim 39, a pharmaceuticallyacceptable salt or solvate thereof or a pharmaceutically acceptablequaternary ammonium salt thereof, and (ii) at least one pharmaceuticallyacceptable excipient.
 46. A pharmaceutical composition according toclaim 43, which contains from 0.5 to 700 mg of said compound.
 47. Apharmaceutical composition which contains (i) an effective amount of acompound according to claim 40, a pharmaceutically acceptable salt orsolvate thereof or a pharmaceutically acceptable quaternary ammoniumsalt thereof, and (ii) at least one pharmaceutically acceptableexcipient.
 48. A pharmaceutical composition according to claim 47, whichcontains from 0.5 to 700 mg of said compound.
 49. A compound accordingto claim 2, which is1-[2-(biphenyl-4-yl)ethyl]-4-(3-trifluoromethylphenyl)-1,2,3,6-tetrahydropyridine,a salt or a solvate thereof.
 50. A pharmaceutical composition comprising(i) an effective amount of a compound according to claim 49, apharmaceutically acceptable salt or solvate thereof, and (ii) at leastone pharmaceutically acceptable excipient.
 51. A pharmaceuticalcomposition according to claim 50, comprising from 0.5 to 700 mg of saidcompound.